HIV Integrase inhibitors

ABSTRACT

The present invention relates to the inhibition of HIV integrase, and to the treatment of AIDS or ARC by administering compounds of the following formula, or a tautomer of said compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof:  
                 
 
     wherein R 1 , R 2  and B 1  are as defined herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. provisionalapplication U.S. Ser. No. 60/339,674, filed Dec. 12, 2001.

BACKGROUND

[0002] Human immunodeficiency virus (HIV) has been identified as theetiological agent responsible for acquired immune deficiency syndrome(AIDS), a fatal disease characterized by destruction of the immunesystem and the inability to fight off life threatening opportunisticinfections. Recent statistics (UNAIDS: Report on the Global HIV/AIDSEpidemic, December 1998), indicate that as many as 33 million peopleworldwide are infected with the virus. In addition to the large numberof individuals already infected, the virus continues to spread.Estimates from 1998 point to close to 6 million new infections in thatyear alone. In the same year there were approximately 2.5 million deathsassociated with HIV and AIDS.

[0003] There are currently a number of antiviral drugs available tocombat the infection. These drugs can be divided into three classesbased on the viral protein they target and their mode of action. Inparticular, saquinavir, indinavir, ritonavir, nelfinavir and amprenavirare competitive inhibitors of the aspartyl protease expressed by HIV.Zidovudine, didanosine, stavudine, lamivudine, zalcitabine and abacavirare nucleoside reverse transcriptase inhibitors that behave as substratemimics to halt viral cDNA synthesis. The non-nucleoside reversetranscriptase inhibitors, nevaripine, delavaridine and efavirenz inhibitthe synthesis of viral cDNA via a non-competitive (or uncompetitive)mechanism. Used alone these drugs are effective in reducing viralreplication. The effect is only temporary as the virus readily developsresistance to all known agents. However, combination therapy has provenvery effective at both reducing virus and suppressing the emergence ofresistance in a number of patients. In the US, where combination therapyis widely available, the number of HIV-related deaths has declined(Palella, F. J.; Delany, K. M.; Moorman, A. C.; Loveless, M. O.; Furher,J.; Satten, G. A.; Aschman, D. J.; Holmberg, S. D. N. Engl. J. Med.1998, 338, 853).

[0004] Unfortunately, not all patients are responsive and a large numberfail this therapy. In fact, approximately 30-50% of patients ultimatelyfail combination therapy. Treatment failure in most cases is caused bythe emergence of viral resistance. Viral resistance in turn is caused bythe rapid turnover of HIV-1 during the course of infection combined witha high viral mutation rate. Under these circumstances incomplete viralsuppression caused by insufficient drug potency, poor compliance to thecomplicated drug regiment as well as intrinsic pharmacological barriersto exposure provides fertile ground for resistance to emerge. Moredisturbing are recent findings which suggest that low-level replicationcontinues even when viral plasma levels have dropped below detectablelevels (<50 copies/ml) (Carpenter, C. C. J.; Cooper, D. A.; Fischl, M.A.; Gatell, J. M.; Gazzard, B. G.; Hammer, S. M.; Hirsch, M. S.;Jacobsen, D. M.; Katzenstein, D. A.; Montaner, J. S.; Richman, D. D.;Saag, M. S.; Schecter, M.; Schoolery, R. T.; Thompson, M. A.; Vella, S.;Yeni, P. G.; Volberding, P. A. JAMA 2000, 283, 381). Clearly there is aneed for new antiviral agents, preferably targeting other viral enzymesto reduce the rate of resistance and suppress viral replication evenfurther.

[0005] HIV expresses three enzymes, reverse transcriptase, an aspartylprotease and integrase, all of which are potential antiviral targets forthe development of drugs for the treatment of AIDS. However, integrasestands out as being the only viral enzyme not targeted by currenttherapy. The integrase enzyme is responsible for insertion of the viralcDNA into the host cell genome, which is a critical step in the virallife cycle. There are a number of discrete steps involved in thisprocess including processing of the viral cDNA by removal of two basesfrom each 3′-terminus and joining of the recessed ends to the host DNA.Studies have shown that in the absence of a functional integrase enzymeHIV is not infectious. Therefore, an inhibitor of integrase would beuseful as a therapy for AIDS and HIV infection.

[0006] A number of inhibitors of the enzyme have been reported. Theseinclude, nucleotide-based inhibitors, known DNA binders, catechols andhydrazide containing derivatives (Neamati, N.; Sunder, S.; Pommier, Y.,Drug Disc. Today, 1997, 2, 487). However, no clinically active compoundhas resulted from these leads. Thus, what is needed is a clinicallyeffective inhibitor of the HIV integrase enzyme.

SUMMARY OF THE INVENTION

[0007] The present invention relates to compounds of Formula I, orpharmaceutically acceptable salts or solvates thereof.

[0008] In Formula I,

[0009] R¹ is

[0010] -aryl,

[0011] —C₁-C₆ alkyl-aryl,

[0012] —C₁-C₆ alkyl-S(O)_(n)-aryl,

[0013] —C₁-C₅ alkyl-O-aryl; or

[0014] wherein R¹ is unsubstituted or substituted with 1-3 R³;

[0015] Each R³ is independently selected from

[0016] —H,

[0017] -halo,

[0018] —CN,

[0019] —C₁-C₆ alkyl,

[0020] —C₃-C₆ cycloalkyl

[0021] —OR⁴,

[0022] —C₁-C₁₀ alkyl-O—R⁴,

[0023] —CO₂R⁵,

[0024] —C₁-C₁₀ alkyl-CO₂R⁵,

[0025] ——N(R⁶)(R⁷),

[0026] —C₁-C₁₀ alkyl-N(R⁶)(R⁷),

[0027] —CON(R⁶)(R⁷),

[0028] —C₁-C₁₀ alkyl-CON(R⁶)(R⁷)

[0029] —S(O)_(n)R⁸,

[0030] —C₁-C₁₀ alkyl-S(O)_(n)R⁸

[0031] —S(O)_(n)N(R⁹)(R¹⁰),

[0032] —C₁-C₁₀ alkyl-S(O)_(n)N(R⁹)(R¹⁰),

[0033] -aryl,

[0034] —O-aryl,

[0035] -heteroaryl,

[0036] —O-heteroaryl,

[0037] —C₁-C₆ alkyl-aryl,

[0038] —C₁-C₆ alkyl-heteroaryl,

[0039] —C(O)-heterocyclic radical,

[0040] —C₁-C₁₀ alkyl-C(O)-heterocyclic radical, or

[0041] —C₁-C₆ haloakyl;

[0042] R² is

[0043] —H,

[0044] —C₁-C₁₀ alkyl,

[0045] —C₃-C₆ cycloakyl,

[0046] —C₁-C₁₀ haloalkyl,

[0047] -aryl,

[0048] -heteroaryl,

[0049] —C₁-C₆ alkyl-aryl,

[0050] —C₁-C₅ alkyl-O-aryl,

[0051] —C₁-C₆ alkyl-heteroaryl,

[0052] —C₁-C₅ alkyl-O-heteroaryl,

[0053] —C₁-C₁₀ alkyl-OR⁴,

[0054] —C₁-C₁₀ alkyl-CO₂R⁵,

[0055] —C₁-C₁₀ alkyl-N(R⁶)(R⁷),

[0056] —C₁-C₁₀ alkyl-CON(R⁶)(R⁷),

[0057] —C₁-C¹⁰ alkyl-S(O)_(n)R⁸,

[0058] —C₁-C¹⁰ alkyl-S(O)_(n)N(R⁹)(R¹⁰), or

[0059] —C₁-C₁₀ alkyl-C(O)-heterocyclic radical;

[0060] Each R⁴ is independently selected from

[0061] —H,

[0062] —C₁-C₆ alkyl,

[0063] —C₃-C₆ cycloalkyl,

[0064] —C₁-C₉ alkyl-CO₂R⁵,

[0065] —C₁-C₉ alkyl-N(R⁶)(R⁷),

[0066] —C₁-C₉ alkyl-CON(R⁶)(R⁷),

[0067] —C₁-C⁹ alkyl-S(O)_(n)R⁸, or

[0068] —C₁-C⁹ alkyl-S(O)_(n)N(R⁹)(R¹⁰);

[0069] Each R⁵ is independently selected from

[0070] —H,

[0071] —C₁-C₆ alkyl,

[0072] —C₃-C₆ cycloalkyl, or

[0073] —C₁-C₆ alkyl-aryl;

[0074] Each R⁶ is independently selected from

[0075] —H,

[0076] —C₁-C₆ alkyl,

[0077] -aryl,

[0078] -heteroaryl,

[0079] —C₁-C₆ alkyl-aryl,

[0080] —C₁-C₆ alkyl-heteroaryl,

[0081] —C(O)—C₁-C₆ alkyl,

[0082] —C(O)-aryl,

[0083] —C(O)—C₁-C₆ alkyl-aryl,

[0084] —C(O)-heteroaryl,

[0085] —C(O)—C₁-C₆ alkyl-heteroaryl,

[0086] —C(NH)NH₂,

[0087] —S(O)_(n)—R⁸, or

[0088] —C₁-C₆ alkyl-CO₂R⁵;

[0089] Each R⁷ is independently selected from

[0090] —H,

[0091] —C₁-C₆ alkyl,

[0092] -aryl, or

[0093] -heteroaryl;

[0094] Each R⁸ is independently selected from

[0095] —C₁-C₆ alkyl,

[0096] -aryl, or

[0097] -heteroaryl;

[0098] Each R⁹ is independently selected from

[0099] —H,

[0100] —C₁-C₆ alkyl,

[0101] —C₁-C₆ alkyl-aryl,

[0102] —C₁-C₆ alkyl-heteroaryl,

[0103] —C(O)—C₁-C₆ alkyl,

[0104] —C(O)-aryl,

[0105] —C(O)—C₁-C₆ alkyl-aryl,

[0106] —C(O)-heteroaryl,

[0107] —C(O)—C₁-C₆ alkyl-heteroaryl,

[0108] -aryl, or

[0109] -heteroaryl;

[0110] Each R¹⁰ is independently selected from

[0111] —H,

[0112] —C₁-C₆ alkyl,

[0113] —C₁-C₆ alkyl-aryl,

[0114] —C₁-C₆ alkyl-heteroaryl,

[0115] -aryl, or

[0116] -heteroaryl;

[0117] R¹¹ is

[0118] —H,

[0119] -aryl,

[0120] -heteroaryl,

[0121] —C₃-C₆ cycloalkyl,

[0122] —C₁-C₆ alkyl,

[0123] —C₁-C₆ alkyl-aryl,

[0124] —C₁-C₆ alkyl-heteroaryl,

[0125] —C₁-C₆ alkyl-CO₂R⁵, or

[0126] —C₁-C₆ alkyl-N(R⁶)(R⁷);

[0127] R¹² is

[0128] —H,

[0129] —C₁-C₆ alkyl,

[0130] -aryl, or

[0131] -heteroaryl;

[0132] R¹³ is

[0133] —H,

[0134] —C₁-C₆ alkyl,

[0135] -aryl, or

[0136] -heteroaryl;

[0137] B¹ is selected from the group consisting of

[0138] n is 0, 1 or 2.

[0139] The present invention also relates to a method of inhibiting HIVintegrase by administering to a patient an effective amount of acompound of Structural Formula Ia, or a pharmaceutically acceptablesalt, solvate or prodrug thereof.

[0140] In Formula Ia, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are asdefined for Formula I, whereas B² is

[0141] The present invention further relates to a method of treatingpatients infected by the HIV virus, or of treating AIDS or ARC, byadministering to the patient an effective amount of a compound ofStructural Formula Ia, or a pharmaceutically acceptable salt, solvate orprodrug thereof.

[0142] Another embodiment includes a pharmaceutical composition, usefulfor inhibiting HIV integrase, or for treating patients infected with theHIV virus, or suffering from AIDS or ARC, which comprises atherapeutically effective amount of one or more of the compounds ofFormula Ia, including pharmaceutically acceptable salts, solvates orprodrugs thereof, and a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

[0143] In the present invention, unless otherwise specified thefollowing definitions apply.

[0144] The numbers in the subscript after the symbol “C” define thenumber of carbon atoms a particular group can contain. For example,“C₁-C₆” means a substituent containing from one to six carbon atoms.

[0145] As used herein, the term “alkyl” means a saturated, straightchain or branched monovalent hydrocarbon radical having the statednumber of carbon atoms. Examples of such alkyl radicals include methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and,where indicated, higher homologs and isomers such as n-pentyl, n-hexyl,2-methylpentyl and the like. Haloalkyl refers to an alkyl radical thatis substituted with one or more halo radicals, such as trifluoromethyl.

[0146] As used herein, the term “cycloalkyl” means a non-aromatic 3-6membered ring. Examples include, cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl.

[0147] Halo means chloro, bromo, iodo or fluoro.

[0148] “Aryl” means an aromatic hydrocarbon having from six to fourteencarbon atoms; examples include phenyl and napthyl, indenyl, azulenyl,fluorenyl and anthracenyl.

[0149] The term “heterocyclic radical” refers to radicals derived frommonocyclic saturated heterocyclic nuclei having 3-6 atoms containing 1-3heteroatoms selected from nitrogen, oxygen or sulfur. Heterocyclicradicals include, for example, piperidinyl, piperazinyl, pyrrolidinyland morpholinyl.

[0150] “Heteroaryl” means a five- or six-membered aromatic ringcontaining at least one and up to four non-carbon atoms selected fromoxygen, sulfur and nitrogen. Examples of heteroaryl include 2-furyl,3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazinyl, 2-thienyl,3-thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl,1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, 1,3,5-triazinyl and1,3,5-trithianyl.

[0151] In a preferred embodiment, compounds of the present inventionthat are useful for treating AIDS have the structure of Formula II.

[0152] In Formula II, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are asdefined for Formula I, while B² is defined as in Formula Ia.

[0153] In yet another embodiment of the present invention, compoundshaving the structure of Formula III, as follows, are preferred chemicalintermediates from which compounds, or pharmaceutically acceptablesalts, solvates or prodrugs, useful for the treatment of AIDS areformed. Even more preferentially, the compounds of Formula III areuseful, themselves, as prodrugs and can be administered as a prodrug toa patient as a compound or in pharmaceutical formulation.

[0154] In Formula III, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹² andR¹³ are as defined for Formula I.

[0155] In a more preferred embodiment, compounds of the presentinvention have the structure of Formula IV, shown below

[0156] wherein:

[0157] Each R¹⁴ is independently selected from

[0158] —CN,

[0159] —H, or

[0160] -halo;

[0161] R¹⁵ is

[0162] —CH₂C(O)N(CH₃)₂ or

[0163] —C₁-C₂ alkyl; and

[0164] B² is as defined for Formula Ia.

[0165] By virtue of its acidic moiety, where applicable, a compound ofFormula I forms salts by the addition of a pharmaceutically acceptablebase. Such base addition salts include those derived from inorganicbases which include, for example, alkali metal salts (e.g. sodium andpotassium), alkaline earth metal salts (e.g. calcium and magnesium),aluminum salts and ammonium salts. In addition, suitable base additionsalts include salts of physiologically acceptable organic bases such astrimethylamine, triethylamine, morpholine, pyridine, piperidine,picoline, dicyclohexylamine, N,N′-dibenzylethylenediamine,2-hydroxyethylamine, bis-(2-hydroxyethyl)amine,tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine,N-benzyl-phenethylamine, dehydroabietylamine, N,N′-bishydroabietylamine,glucamine, N-methylglucamine, collidine, quinine, quinoline,ethylenediamine, ornithine, choline, N,N′-benzylphenethylamine,chloroprocaine, diethanolamine, diethylamine, piperazine,tris(hydroxymethyl)aminomethane and tetramethylammonium hydroxide andbasic amino aids such as lysine, arginine and N-methylglutamine. Thesesalts may be prepared by methods known to those skilled in the art.

[0166] Salts of an amine group may also comprise quaternary ammoniumsalts in which the amino nitrogen carries a suitable organic group suchas an alkyl, alkenyl, alkynyl or arylalkyl moiety.

[0167] Compounds of Formula I, which are substituted with a basic group,may exist as salts formed through acid addition. The acid addition saltsare formed from a compound of Formula I and a pharmaceuticallyacceptable inorganic acid, including but not limited to hydrochloric,hydrobromic, hydroiodic, sulfuric, phosphoric, or organic acid such asp-toluenesulfonic, methanesulfonic, acetic, benzoic, citric, malonic,fumaric, maleic, oxalic, succinic, sulfamic, or tartaric. Thus, examplesof such pharmaceutically acceptable salts include chloride, bromide,iodide, sulfate, phosphate, methanesulfonate, citrate, acetate,malonate, fumarate, sulfamate, and tartrate.

[0168] Certain compounds of Formula I, and their salts, may also existin the form of solvates with water, for example hydrates, or withorganic solvents such as methanol, ethanol or acetonitrile to form,respectively, a methanolate, ethanolate or acetonitrilate. The presentinvention includes each solvate and mixtures thereof.

[0169] This invention also encompasses pharmaceutically acceptableprodrugs of the compounds of Formula I. Prodrugs are derivatives of thecompounds of the invention which have chemically or metabolicallycleavable groups and become, by solvolysis or under physiologicalconditions, the compounds of the invention which are pharmaceuticallyactive in vivo. A prodrug of a compound of Structural Formula I may beformed in a conventional manner with a functional group of the compoundssuch as with an amino, hydroxy or carboxy group. The prodrug derivativeform often offers advantages of solubility, tissue compatibility, ordelayed release in a mammalian organism (see, Bundgaard, H., Design ofProdrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs includeacid derivatives well known to practitioners of the art, such as, forexample, esters prepared by reaction of the parent acidic compound witha suitable alcohol, or amides prepared by reaction of the parent acidcompound with a suitable amine. Simple aliphatic or aromatic estersderived from acidic groups pendent on the compounds of this inventionare preferred prodrugs. In some cases it is desirable to prepare doubleester type prodrugs such as (acyloxy) alkyl esters or(alkoxycarbonyl)oxy)alkyl esters. Examples of prodrugs of compounds ofthe present invention include the compounds 1-A, 2-A, 3-C, 4-B, 5-B,6-C, 7-C, 8-C, 9-C, 10-A, 11-C, 12-C, 13-C, 14-C, 15-C, 16-C, 17-C,18-C, 19-C, 20-C, 21-C, 22-A, 22-B, 23-C, 25-C, 26-C, 27-C, 28-C, 29,30-C, 31-C, 32-D, 32-E, 33, 34-C, 35-C, 36, 37-D, 38-61.

[0170] In addition, a compound of Structural Formula I, or a salt,solvate or prodrug thereof, may exhibit polymorphism. The presentinvention also encompasses any such polymorphic form.

[0171] Certain compounds of Structural Formula I may contain one or morechiral centers and exist in different optically active forms. Whencompounds of Structural Formula I contain one chiral center, thecompounds exist in two enantiomeric forms. The present inventionincludes both enantiomers and mixtures of enantiomers such as racemicmixtures. The enantiomers may be resolved by methods known to thoseskilled in the art, for example, by formation of diastereoisomeric saltswhich may be separated by crystallization, gas-liquid or liquidchromatography, selective reaction of one enantiomer with anenantiomer-specific reagent. It will be appreciated that where thedesired enantiomer is converted into another chemical entity by aseparation technique, then an additional step is required to form thedesired enantiomeric form. Alternatively, specific enantiomers may besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by converting one enantiomer intothe other by asymmetric transformation.

[0172] Certain compounds of Structural Formula I may also exist indifferent stable conformational forms which may be separable. Torsionalasymmetry due to restricted rotation about an asymmetric single bond,for example because of steric hindrance or ring strain, may permitseparation of different conformers. The present invention includes eachconformational isomer of compounds of Structural Formula I and mixturesthereof.

[0173] Certain compounds of Structural Formula I may exist inzwitterionic form and the present invention includes each zwitterionicform of compounds of Structural Formula I and mixtures thereof.

[0174] The compounds of this invention can also exist as tautomers;therefore the present invention also includes all tautomeric forms.

[0175] The compounds of Formula Ia are useful in the inhibition of HIVintegrase, the prevention or treatment of infection by the humanimmunodeficiency virus and the treatment of consequent pathologicalconditions such as AIDS or ARC. The treatment involves administering toa patient, in need of such treatment, a compound of Formula Ia, or apharmaceutically acceptable salt, solvate or prodrug thereof, or apharmaceutical composition comprising a pharmaceutical carrier and atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, solvate or prodrug therefor.

[0176] It will be appreciated by those skilled in the art that referenceherein to treatment extends to prophylaxis as well as the treatment ofestablished infections or symptoms. This includes initiating treatmentpre- and post-exposure to the virus. In addition, the present inventioncan be administered in conjunction with other anti-HIV agents (HIVprotease inhibitors, nucleoside reverse transcriptase inhibitors,non-nucleoside reverse transcriptase inhibitors, and HIV-entryinhibitors), immunomodulators, antiinfectives and/or vaccines.

[0177] The compounds of the present invention are also useful in thepreparation and execution of screening assays for antiviral compounds.Further, the compounds of the present invention are useful inestablishing or determining the binding site of other antiviralcompounds to HIV integrase, for example, by competitive inhibition.

[0178] The compounds of the present invention may be administeredorally, parenterally (including subcutaneous injections, intravenous,intramuscular, intrasternal injection or infusion techniques), byinhalation spray or rectally, in dosage unit formulations containingconventional non-toxic pharmaceutically acceptable carriers, adjuvantsand vehicles.

[0179] This invention also provides a pharmaceutical composition for usein the above described therapeutic method. A pharmaceutical compositionof the present invention comprises an effective amount of a compound ofFormula I in association with a pharmaceutically acceptable carrier,excipient or diluent.

[0180] The active ingredient in such formulations comprises from 0.1percent to 99.9 percent by weight of the formulation. By“pharmaceutically acceptable” it is meant that the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

[0181] The present pharmaceutical compositions are prepared by knownprocedures using well known and readily available ingredients. Thecompositions of this invention may be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures well known in theart. In making the compositions of the present invention, the activeingredient will usually be admixed with a carrier, or diluted by acarrier, or enclosed within a carrier which may be in the form of acapsule, sachet, paper or other container. When the carrier serves as adiluent, it may be a solid, semi-solid or liquid material which acts asa vehicle, excipient or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, beadlets,lozenges, sachets, elixers, suspensions, emulsions, solutions, syrups,aerosols, (as a solid or in a liquid medium), soft and hard gelatincapsules, suppositories, sterile injectable solutions, sterile packagedpowders and the like.

[0182] The compound can be administered by a variety of routes includingoral, rectal, transdermal, subcutaneous, intravenous, intramuscular andintranasal.

[0183] When administered orally, these compositions are preparedaccording to techniques well-known in the art of pharmaceuticalformulation. For oral administration, the compound is typicallyformulated with excipients such as binders, fillers, lubricants,extenders, diluents, disintegration agents and the like as are known inthe art.

[0184] For parenteral administration, the compound is formulated inpharmaceutically acceptable non-toxic, parenterally-acceptable diluentsor solvents, such as mannitol, 1,3-butanediol, water, 5 percentdextrose, Ringer's solution or isotonic sodium chloride solution, orsuitable dispersing or wetting and suspending agents, such as sterile,bland, fixed oils, including synthetic mono- or diglycerides, and fattyacids, including oleic acid.

[0185] A compound of the present invention, or a salt or solvatethereof, can be formulated in unit dosage formulations comprising a dosebetween about 0.1 mg and about 1000 mg, or more, according to theparticular treatment involved. An example of a unit dosage formulationcomprises 5 mg of a compound of the present invention as apharmaceutically acceptable salt in 20 mL of isotonic saline containedin a sterile ampoule.

[0186] The compounds of the present invention can also be administeredto humans in a dosage range of 1 to 100 mg/kg body weight in divideddoses. One preferred dosage range is 1 to 20 mg/kg body weight orally individed doses. It will be understood, however, that the specific doselevel and frequency of dosage for any particular patient may be variedand will depend upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the route of administration, the age, body weightgeneral health, sex,diet, mode and time of administration, rate ofexcretion, drug combination, the severity of the particular condition,and the host undergoing therapy.

[0187] General methods useful for the synthesis of compounds embodied inthis invention are shown below. The preparations shown below aredisclosed for the purpose of illustration and are not meant to beinterpreted as limiting the processes to make the compounds by any othermethods

[0188] It will be appreciated by those skilled in the art that a numberof methods are available for the preparation of the compounds of thepresent invention as provided by Structural Formula I. A compound ofStructural Formula I may be prepared by processes which includeprocesses known in the chemical art for the production of structurallyanalogous compounds or by a novel process described herein. A processfor the preparation of a compound of Structural Formula I (or apharmaceutically acceptable salt thereof) and novel intermediates forthe manufacture of a compound of Formula I, as defined above, providefurther features of the invention and are illustrated by the followingprocedures in which the meanings of the generic radicals are as definedabove, unless otherwise specified. It will be recognized that it may bepreferred or necessary to prepare a compound of Formula I in which afunctional group is protected using a conventional protecting group, andthen to remove the protecting group to provide the compound of FormulaI.

[0189] Thus, there is provided a process for preparing a compound ofFormula I (or a pharmaceutically acceptable salt thereof) as provided inany of the above descriptions which is selected from any of thosedescribed in the examples, including the following.

[0190] Schemes I and II illustrate the synthesis of non-commerciallyavailable N-,O-disubstituted hydroxylamines I-C and II-C. In Scheme Ibenzaldehyde, I-A, substituted with 1-3 R³ groups is condensed withhydroxylamine or an O-substituted hydroxylamine derivative. In the eventthat the hydroxyl group is unsubstituted (R²═H), this position can befunctionalized via nucleophilc attack on an appropriately substitutedR²—X electophile (X═Cl, Br, I, —OTs, —OMs, —OTf). It will be appreciatedby those skilled in the art that this reaction can be conducted in anumber of different ways. The resulting oxime I-B can be easily reducedto the corresponding N-,O-disubstituted hydroxylamine using sodiumcyanoborohydride, or a related reducing agent such as triethylsilane,under acidic conditions. In scheme II, and O-substituted hydroxyl amineis acylated wit Boc-anhydride to form intermediate II-A. This can bereacted with an appropriately substituted R¹CH₂—X electophile (X═Cl, Br,I, —OTs, —OMs or —OTf) under basic conditions to yield the Boc-protectedN-,O-disubstituted hydroxylamine II-B. The Boc-protecting group isremoved to yield N-,O-disubstituted hydroxylamine II-C. It will beappreciated by those skilled in the art that other protecting groups oracylating agents can be used in place of the Boc-group to effect thesame transformation.

[0191] As shown in Scheme III, the N-,O-disubstituted hydroxylamines 5are then coupled to dioxolane III-A or III-B using standard amide bondforming chemistry. The syntheses of the dioxolanes III-A and III-B aredescribed in the exemplification section. The resulting intermediatesIII-C and III-D are saponified with NaOH or LiOH to yield integraseinhibitors III-E and III-F.

[0192] Alternative synthetic methods useful for producing the compoundsdescribed in this invention are illustrated in Scheme IV. The acylatedN,O-disubstituted hydroxylamine IV-A can be synthesized startingdirectly from II-C, synthesized as shown previously or via a differentroute which commences with compound IV-C. IV-C can be reacted withN,O-bis-Boc-hydroxylamine to yield intermediate IV-D. After removal ofthe Boc-protecting groups this is acylated with acetyl chloride oracetic acid anhydride under standard amide bond forming conditions toproduce IV-F. The hydroxyl group is then functionalized via nucleophilicsubstitution of an appropriately activated R²—X (X═Cl, Br, I, —OTs, —OMsor OTf) yielding IV-A. This intermediate is condensed with dimethyloxalate in a Claisen reaction carried out using lithiumbis(trimethylsilyl)amide. Ester IV-B is saponified using NaOH or LiOH toyield integrase inhibitors III-F.

[0193] Starting from intermediate 20-C, Scheme V, illustrates thesynthesis of compounds 20, 22-A, 22-B, 22 and 24.

[0194] In Scheme VI compound 22-A is converted to the corresponding acidchloride, compound 38-A, using oxalyl chloride. This is subsequentlyreacted with amine VI-A using a suitable base catalyst to yieldintermediate VI-B. This intermediate is hydrolyzed under basicconditions (LiOH) to produce inhibitors VI-C.

[0195] Exemplification

[0196] The specific examples that follow illustrate the syntheses of thecompounds of the instant invention, and are not to be construed aslimiting the invention in sphere or scope. The methods may be adapted tovariations in order to produce compounds embraced by this invention butnot specifically disclosed. Further, variations of the methods toproduce the same compounds in somewhat different manner will also beevident to one skilled in the art.

[0197] In the following experimental procedures, all temperatures areunderstood to be in Centigrade (C.) when not specified. The nuclearmagnetic resonance (NMR) spectral characteristics refer to chemicalshifts (δ) expressed in parts per million (ppm) versus tetramethylsilane(TMS) as reference standard. The relative area reported for the variousshifts in the proton NMR spectral data corresponds to the number ofhydrogen atoms of a particular functional type in the molecule. Thenature of the shifts as to multiplicity is reported as broad singlet (bsor br s), broad doublet (bd or br d), broad triplet (bt or br t), broadquartet (bq or br q), singlet (s), multiplet (m), doublet (d), quartet(q), triplet (t), doublet of doublet (dd), doublet of triplet (dt), anddoublet of quartet (dq). The solvents employed for taking NMR spectraare acetone-d₆ (deuterated acetone), DMSO-d₆(perdeuterodimethylsulfoxide), D₂O (deuterated water), CDCl₃(deuterochloroform) and other conventional deuterated solvents.

[0198] The abbreviations used herein are conventional abbreviationswidely employed in the art. Some of which are: calcd (calculated); DMSO(dimethylsulfoxide); EtOAc (ethyl acetate); HPLC (high-pressure liquidchromatography); LC/MS (liquid chromatography, mass spectroscopy); LDA(lithium diisopropyl amide); LiHMDS (lithium bis(trimethylsilyl)amide);SiO₂ (silica gel); THF (tetrahydrofuran), TFA (trifluoroacetic acid), Me(methyl), Et (ethyl), Ph (phenyl), tBuOK (potassium tert-butoxide),NaOMe (sodium methoxide), NaOEt (sodium ethoxide), Boc(tert-butoxycarbonyl), and DEAD (diethylazo dicarboxylate).

Method A

[0199] Compound A-1: (S)-(+)-2,2-Dimethyl-5-oxo-1,3-dioxolane-4-aceticacid, tert-butyldiphenylsilyl ester

[0200] A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-aceticacid (2.08 g, 11.9 mmol) in dry dichloromethane (20 ml) was treated withtriethylamine (1.83 ml, 13.1 mmol) followed by a solution oft-butylchlorodiphenylsilane (3.44 g, 12.5 mmol) in dichloromethane (5ml) added dropwise over 5 minutes. After 3 hours at 22° C., the reactionmixture was diluted with toluene (250 ml) washed with water, saturatedsodium bicarbonate, brine and dried over magnesium sulfate. Evaporationof the solvent under reduced pressure and chromatography of the residueon silica gel (4×12 cm) using a mixture of toluene and ethyl acetate(0-2%) as eluent gave 4.90 g (99% yield) of the title material as aclear oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.13 (s, 9), 1.58 (s, 3), 3.05 (m,2), 4.79 (dd, 1, J=4, 7), 7.4-7.8 (m, 10).

[0201] Compound A-2: 4-Bromo-2,2-dimethyl-5-oxo-1,3-dioxolane-4-aceticacid, tert-butlydiphenylsilyl ester

[0202] A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-aceticacid, tert-butyldiphenylsilyl ester (21.65 g, 52.4 mmol) in carbontetrachloride (160 ml) was treated with N-bromosuccinimide (9.35 g, 52.4mmol) and 2,2′-azobisisobutyronitrile (200 mg) and the resulting mixturewas heated under reflux (bath temperature 85° C.) while irradiating witha 500 watt lamp. After 10 minutes, the reaction mixture was cooled andthe succinimide was filtered. The solvent was evaporated under vacuum togive the title bromide as a light yellow oil (˜26 g) which was usedimmediately for the next step. ¹H NMR (400 MHz, CDCl₃) δ: 1.12 (s, 9),1.41 (s, 3), 1.80 (s, 3), 3.80 (m, 2), 7.3-7.7 (m, 10).

[0203] Compound A-3:(Z)-2,2-Dimethyl-5-(tert-butyldiphenylsilyloxycarbonyl-methylene)-1,3-dioxolan-4-one

[0204] A solution of 4-bromo-2,2-dimethyl-5-oxo-1,3-dioxolane-4-aceticacid, tert-butyldiphenylsilyl ester (˜26 g, 52.4 mmol) in drytetrahydrofuran (160 ml) was cooled to 0° C. and treated dropwise over 5minutes with 1,8-diazabicyclo [5,4,0] undec-7-ene (12.7 g, 78.8 mmol)and the resulting mixture was stirred at 5° C. for 1.5 hour. The solidformed was filtered and washed with a small amount of tetrahydrofuran.The filtrate was used as such for the next step.

[0205] Alternatively, the reaction mixture can be diluted with toluene,washed with water, saturated sodium bicarbonate, brine and dried(magnesium sulfate). Evaporation of the solvent gave an oil which waschromatographed on silica gel using a mixture of toluene and ethylacetate (0-2%) as eluent. The title ester was obtained as an oil in30-50% yield. ¹HNMR (400 MHz, CDCl₃) δ: 1.16 (s, 9), 1.76 (s, 6), 5.97(s, 1), 7.4-7.8 (m, 10).

[0206] Compound III-A:(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetic acid

[0207] A solution of pure (Z)-2,2dimethyl-5-(t-butyldiphenylsilyloxy-carbonylmethylene)-1,3-dioxolan-4-one(2.80 g, 6.82 mmol) in tetrahydrofuran (40 ml) was treated at 22° C.with acetic acid (2 ml) followed by 6.8 ml of a 1 M solution oftetrabutylammonium fluoride in tetrahydrofuran. After 15 minutes at 22°C., the reaction mixture was diluted with ethyl acetate, washed withwater, brine and dried (magnesium sulfate). The solvent was concentratedunder reduced pressure and the residue was triturated with toluene togive 1.00 g (85% yield) of the title compound as a white crystallinematerial: mp 203-204° C. (dec.). IR (KBr) v max (cm⁻¹): 1805, 1707 and1662. ¹H NMR (400 MHz, CDCl₃) δ: 1.78 (s, 6), 5.89 (s, 1). Anal. calcdfor C₇H₈O₅: C, 48.84; H, 4.68; Found: C, 48.84; H, 4.65.

[0208] Preparation of(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetic acid from crude A-3

[0209] A solution of the crude(Z)-2,2-dimethyl-5-(tert-butyldiphenylsilyloxycarbonylmethylene)-1,3-dioxolan-4-one (52.4 mmol) in tetrahydrofuran (200 ml)was treated with acetic acid (13 ml) followed with 50 ml of a 1 Msolution of tetrabutylammonium fluoride in tetrahydrofuran. After 15minutes at 22° C., the reaction mixture was filtered and the filtratewas concentrated in vacuo. Trituration of the residue with toluene gave6.3 g (70% yield for three steps) of the title material as a white solid(>95% pure by ¹HNMR).

Method B

[0210] Compound B-1: (+)-2,2-Dimethyl-5-oxo-1,3-dioxolane-4-acetic acid,tert-butyldimethylsilyl ester

[0211] A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-aceticacid (13.20 g, 75.8 mmol) in N,N-dimethylformamide (25 ml) was treatedat 22° C. with imidazole (10.56 g, 0.155 mmol) followed bytert-butyldimethylsilyl chloride (12.0 g, 79.6 mmol) and the resultingmixture was stirred at 22° C. for 18 hours. The reaction mixture wasthen diluted with toluene (500 ml), washed with water (3 times),saturated sodium bicarbonate and brine. After drying (magnesiumsulfate), the solvent was evaporated under reduced pressure to give anoil. Distillation under vacuum gave 20.9 g (96% yield) of the titlematerial as a clear oil : Bp 80-90° C./0.1 torr (bulb to bulbdistillation, air bath temperature). ¹H NMR (400 MHz, CDCl₃) δ: 0.33 (s,3), 0.36 (s, 3), 1.00 (s, 9), 1.11 (s, 3), 1.37 (s, 3), 2.72 (m, 2),4.35 (dd, 1, J=4, 6).

[0212] Compound B-2: 4-Bromo-2,2-dimethyl-5-oxo-1,3-dioxolane-4-aceticacid, tert-butyldimethylsilyl ester

[0213] A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-aceticacid, t-butyldimethylsilyl ester (20.9 g, 72.4 mmol) in carbontetrachloride (200 ml) was treated with N-bromosuccinimide (14.18 g,79.6 mmol) and 2,2′-azobisisobutyronitrile (0.30 g) and the resultingmixture was heated under reflux while irradiating with a 500 W lamp.After ˜5 minutes, a mild exothermic reaction was observed and themixture was heated for an additional 5 minutes. The reaction mixture wasthen cooled in an ice bath and the floating succinimide was filtered andwashed with a small amount of carbon tetrachloride. The filtrate wasused immediately as such for the next step. ¹H NMR (400 MHz, CDCl₃) δ:0.27 (s, 3), 0.28 (s, 3), 0.94 (s, 9), 1.66 (s, 3), 1.84 (s, 3), 3.62(m, 2).

[0214] Compound B-3:(Z)-2,2-Dimethyl-5-(tert-butyldimethylsilyloxycarbonyl-methylene)-1,3-dioxolane

[0215] The solution of crude4-bromo-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid,tert-butyldimethylsilyl ester (72.4 mmol) in carbon tetrachloride (˜220ml) was cooled to 0-5° C. and treated dropwise over 10 minutes and undergood stirring with a solution of 1,8-diazabicyclo [5,4,0] undec-7-ene(12.1 g, 79.6 mmol) in dry tetrahydrofuran (125 ml). A heavy precipitatewas formed which gradually became a granular solid. After 1 h, the solidobtained was filtered and washed with a small amount of tetrahydrofuran.The filtrate was concentrated under reduced pressure to give a lightorange oil which was used as such for the next step.

[0216] Compound III-A:(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetic acid

[0217] The crude(Z)-2,2-dimethyl-5-(tert-butyldimethylsilyloxycarbonylmethylene)-1,3-dioxolan-4-one(72.4 mmol) in tetrahydrofuran (50 ml) was treated at 22° C. with aceticacid (13 ml, 0.227 mmol) followed by 73 ml (73.0 mmol) of a 1M solutionof tetrabutylammonium fluoride in tetrahydrofuran. After 1 h at 22° C.,the reaction mixture was diluted with ethyl acetate (500 ml), washedwith water, brine and dried (anhydrous magnesium sulfate). Evaporationof the solvent under reduced pressure and trituration of the residualsolid with toluene (50 ml) gave 7.70 g (62% yield for 3 steps) of thetitle Z-isomer as a white crystalline solid. Concentration of the motherliquors yielded another 0.2 g of a 75:25 mixture of Z and E isomers.Z-Isomer; ¹H NMR (400 MHz, CDCl₃) δ: 1.78 (s, 3), 5.89 (s, 1). E-Isomer:¹H NMR (400 MHz, CDCl₃) δ: 1.80 (s, 3), 6.03 (s, 1).

Method C

[0218] Compound III-B (2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride

[0219] A mixture of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-aceticacid (0.50 g, 2.9 mmol) in dry dichloromethane (10 ml) was treated at22° C. with oxalyl chloride (0.5 ml, 5.8 mmol) followed by a trace(capillary) of N,N-dimethylformamide. After 1 h at 22° C., the clearsolution was concentrated in vacuo to give 0.55 g (quantitative) of thetitle acid chloride as a white crystalline solid.

EXAMPLE 1

[0220] Compound 1-A:N-Benzyl-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide

[0221] A solution of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride (0.33 g, 1.74 mmol) in dichloromethane (5 ml) was addeddropwise to a cold (0-5° C.) mixture of N-benzyl-O-methyl-hydroxylalmine(0.288 g, 2.1 mmol) (Keck, G. E. Wager, T. T.; McHardy, S. F.Tetrahedron, 55, 1999, 11755-11772) and pyridine (0.21 ml, 2.6 mmol) indichloromethane (10 ml). The cooling bath was then removed and thesolution was stirred at 22° C. for 1.5 hours. The reaction mixture wasthen quenched by the addition of water and ethyl acetate. The organicphase was washed successively with 0.1 N hydrochloric acid, saturatedsodium bicarbonate, brine and dried (magnesium sulfate). Evaporation ofthe solvent and chromatography of the residue on silica gel(toluene-ethyl acetate, 75:25) gave 0.482 g (94% yield) of the titleamide as white crystals:

[0222] mp 109-110° C. (ethyl acetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ(ppm): 1.80 (6H, s), 3.67 (3H, s), 4.84 (2H, s), 6.41 (1H, s), 7.29-7.37(5H, m). Anal. calcd for C₁₅H₁₇NO₅: C 61.84, H 5.88, N 4.80; Found: C61.74, H 5.94, N 4.76.

[0223] Compound 1: 3-(Benzyl-methoxy-carbamoyl)-2-hydroxy-acrylic acid

[0224] A solution ofN-benzyl-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide(0.267 g, 0.917 mmol) in tetrahydrofuran (10 ml) was treated at 22° C.with 2 ml (2 mmol) of 1 M aqueous sodium hydroxide. After 1 h, thereaction mixture was acidified with 1N hydrochloric acid and extractedwith ethyl acetate. The organic phase was washed with brine, dried(magnesium sulfate) and the solvent evaporated in vacuo to give 0.220 g(95% yield) of the title material as a white solid.

[0225]¹HNMR 400 MHz (CDCl₃) δ (ppm) : 3.70 (3H, s), 4.85 (2H, s), 6.57(1H, s), 7.32-7.37 (5H, m).

EXAMPLE 2

[0226] Compound 2-A:N-Benzyl-N-benzyloxy-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetamide

[0227] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with N,O-dibenzyl-hydroxylamine (Bhat, J. I., Clegg, W.;Maskill, H.; Elsegood, M. R. J.; Menner, I. D.; Miatt, P. C. J. Chem.Soc. Perkin Trans. 2, 2000, 1435-1446) as described in the preparationof compound 1-A gave the title amide as white crystals (92% yield): mp107-108° C. (ethyl acetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.72(6H, s), 4.76 (2H, s), 4.84 (2H, s), 6.36 (1H, s), 7.28-7.38 (10H, m).HRMS (MAB N₂) calculated for C₂₁H₂₁NO₅[M⁺]: 367.141973: Found:367.140292.

[0228] Compound 2: 3-(Benzyl-benzyloxy-carbamoyl)-2-hydroxy-acrylic acid

[0229] Saponification of(N-benzyl-N-benzyloxy-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetamideas described in the preparation of compound 1 gave the title material asa white solid (93% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm) : 4.80 (2H, s),4.83 (2H, s), 6.57 (1H, s), 7.19-7.43 (10H, m).

EXAMPLE 3

[0230] Compound 3-A: 4-Fluoro-benzaldehyde-O-methyl-oxime

[0231] A solution of methoxylamine hydrochloride (13.4 g, 0.16 mol) in amixture of water (150 ml) and tetrahydrofuran (50 ml) was treated withCT-2695-NP sodium acetate (11.2 g, 0.136 mol) followed by4-fluorobenzaldehyde (11.57 g, 93.2 mmol) and the resulting mixture wasstirred at 22° C. for 4 hours. The reaction mixture was then dilutedwith ether, washed with brine and dried over anhydrous magnesiumsulfate. Evaporation of the solvent under reduced pressure gave 14.3 gof the crude title material as a clear oil which was used as such forthe next step. Distillation of an aliquot in vacuo gave a clear oil; bp45-50° C./0.5 torr. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.99 (3H, s), 7.09(2H, m), 7.6 (2H, m), 8.06 (1H, s).

[0232] Compound 3-B: N-(4-Fluoro-benzyl)-O-methyl-hydroxylamine

[0233] A solution of 4-fluorobenzaldehyde-O-methyloxime (93.2 mmol) indichloromethane (150 ml) was treated with sodium cyanoborohydride (9.18g, 0.146 mol) followed by 120 ml of 2 N hydrochloric acid in methanoladded dropwise over 30 minutes. After 96 h at 22° C., the solvent wasevaporated under reduce pressure and the residue was slurried with waterand the pH was adjusted to 9 with 2 N aqueous sodium hydroxide. Theaqueous phase was extracted twice with dichloromethane and the combinedorganic extracts were washed with brine, dried (magnesium sulfate) andconcentrated under reduced pressure. The residual oil waschromatographed on silica gel (elution toluene-ethyl acetate 0-10%) andgave 5.92 g (41% yield) of the title amine as a clear oil. ¹HNMR 400 MHz(CDCl₃) δ (ppm): 3.49 (3H, s), 4.01 (2H, s), 5.69 (1H, broad s), 7.01(2H, m), 7.31 (2H, m). The hydrochloride salt was obtained as a whitesolid: mp 170-171° C. Anal. calcd for C₈H₁₀FNO—HCl: C, 50.14; H, 5.78;N, 7.31. Found: C, 50.31; H, 5.80; N, 7.26

[0234] In an alternative procedure a solution of 4-fluorobenzaldehydeO-methyloxime (0.82 g, 5.35 mmol) in acetic acid ( 8 ml ) was treated at10° C. with sodium cyanoborohydride (0.67 g, 10.7 mmol) added in smallportions over 10 min and the resulting solution was stirred at 25° C.for 18 h. The solvent was evaporated under reduced pressure(co-evaporation with toluene twice) and the residue was slurried withwater and the pH was adjusted to 9 with 2 N aqueous sodium hydroxide.The aqueous phase was extracted twice with ether and the combinedorganic extracts were washed with brine, dried (magnesium sulfate) andconcentrated under reduced pressure. The residual oil waschromatographed on silica gel (elution hexane-ethyl acetate, 8:2) anddistilled in vacuo to give 0.62 g (75% yield) of the title amine as aclear oil.

[0235] Compound 3-C:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide

[0236] A solution of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride (2.45 g, 12.9 mmol) in dichloromethane (15 ml) was addeddropwise over 10 minutes to a cold (0-5° C.) mixture ofN-4-fluorobenzyl-O-methyl-hydroxylamine (2.0 g, 12.9 mmol) and pyridine(2.1 ml, 25.7 mmol) in dichloromethane (50 ml). The cooling bath wasthen removed and the solution was stirred at 22° C. for 30 minutes. Thereaction mixture was then quenched by the addition of water and ethylacetate. The organic phase was washed successively with 0.1 Nhydrochloric acid, saturated sodium bicarbonate, brine and dried(magnesium sulfate). Evaporation of the solvent and chromatography ofthe residue on silica gel (toluene-ethyl acetate, 8:2) gave 3.72 g (93%yield) of the title amide as white crystals after recrystallization fromethyl acetate/hexanes. Differential scanning calorimetry shows a sharpendotherm at 107° C.

[0237]¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.75 (6H, s), 3.68 (3H, s), 4.79(2H, s), 6.38 (1H, s), 7.0 (2H, m), 7.34 (2H, m). ¹³CNMR 100 MHz (CDCl₃)δ (ppm): 26.81, 48.43, 63.03, 94.48, 114.22, 115.31, 115.56, 130.47,132.03, 146.95, 161.21, 162.46, 163.65, 164.43. ¹⁹FNMR 377 MHz(CDCl₃) δ(ppm): 114.97.

[0238] Anal. calcd for C₁₅H₁₆FNO₅: C, 58.25; H, 5.21; N, 4.52; Found: C,58.33; H, 5.38; N, 4.51.

[0239] Compound 3:3-[(4-Fluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid

[0240] A solution of2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide(3.65 g, 11.8 mmol) in tetrahydrofuran (150 ml) was treated at 15° C.with 35 ml (35 mmol) of 1 M aqueous sodium hydroxide. After 30 minutes,the reaction mixture was acidified with 1N hydrochloric acid (65 ml) andextracted with ethyl acetate. The organic phase was washed with brine,dried (magnesium sulfate) and evaporated in vacuo to give a white solid.Recrystallization from ethyl acetate and hexane gave 3.04 g (96% yield)of the title material as white needles; mp 129° C. (dec.). ¹HNMR 400 MHz(CDCl₃) δ (ppm): 3.73 (3H, s), 4.84 (2H, s), 6.57 (1H, s), 7.07 (2H,mn), 7.34 (2H, m). ¹³CNMR (enol form) 125 MHz (DMSO-d₆) δ (ppm): 47.08,63.05, 93.35, 130.61, 130.83, 130.90, 132.86, 132.89, 133.14, 133.16,161.02, 161.38, 163.32, 163.81, 170.97. Anal. calcd for C₁₂H₁₂FNO₅: C,53.53; H, 4.49; N, 5.20; Found: C, 53.78; H, 4.30; N, 4.90.

EXAMPLE 4

[0241] Compound 4-A: N-(3,4-Dichloro-benzyl)-O-methyl-hydroxylamine

[0242] Reaction of 3,4-dichlorobenzaldehyde with methoxylaminehydrochloride followed by reduction with sodium cyanoborohydride asdescribed in the preparation of compounds 3-A and 3-B gave the titlehydroxylamine as a clear oil. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.48 (3H,s), 3.99 (2H, s), 5.74 (1H, broad s), 7.20 (1H, dd, J=2.0 Hz and J=8.1Hz), 7.40 (1H, d, J=8.1 Hz), 7.47 (1H, d, J=2.0 Hz).

[0243] Compound 4-B:N-(3,4-Dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide

[0244] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with N-3,4-dichlorobenzyl-O-methyl-hydroxylamine as describedin the preparation of compound 1-A gave the title amide as a white solid(94% yield): mp 119-120° C. (ethyl acetate-hexane). ¹HNMR 400 MHz(CDCl₃) δ (ppm): 1.76 (6H, s), 3.71 (3H, s), 4.72 (2H, s), 6.38 (1H, s),7.20 (1H, dd, J=2.0 Hz and J=8.5 Hz), 7.40 (1H, d, J=8.5 Hz), 7.46 (1H,d, J=2.0 Hz). Anal. calcd for C₁₅H₁₅Cl₂NO₅: C, 50.02; H, 4.20; N, 3.89.

[0245] Found: C, 50.12; H, 4.12; N, 3.80.

[0246] Compound 4:3-[(3,4-Dichloro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid

[0247] Saponification ofN-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamideas described in the preparation of compound 1 gave the title material asa white solid (96% yield). ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): mixture ofrotamers and keto-enol forms: 3.75 (3H, s), 4.90 (2H, s), 6.31 (1H, s),7.28 (1H, dd, J=2.0 Hz and J=8.5 Hz,), 7.57 (1H, d, J=2.0 Hz), 7.62 (1H,d, J=8.5 Hz). HRMS (MAB N₂) calculated for C₁₂H₁₁Cl₂NO₅[M⁺]: 319.001428:Found: 319.001699.

EXAMPLE 5

[0248] Compound 5-A: N-(3-Chloro-4-fluoro-benzyl)-O-methyl-hydroxylamine

[0249] Reaction of 3-chloro-4-fluorobenzaldehyde with methoxylaminehydrochloride followed by reduction with sodium cyanoborohydride asdescribed in the preparation of compounds 3-A and 3-B gave the titlehydroxylamine as a clear oil. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.48 (3H,s), 3.98 (2H, s), 5.72 (1H, broad s), 7.10 (1H, t), 7.22 (1H, mn), 7.42(1H, m).

[0250] Compound 5-B:N-(3-Chloro-4-fluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide

[0251] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with N-(3-chloro-4-fluorobenzyl)-O-methyl-hydroxylamine asdescribed in the preparation of compound 1-A gave the title amide as awhite solid (91% yield): mp 110-111° C. (ethyl acetate-hexane). ¹HNMR400 MHz (CDCl₃) δ (ppm): 1.76 (6H, s), 3.71 (3H, s), 4.75 (2H, s), 6.38(1H, s), 7.09 (1H, t, J=8.8 Hz), 7.23 (1H, m), 7.41 (1H, dd, J=2.4 Hzand J=6.8 Hz). Anal. calcd for C₁₅H₁₅ClFNO₅: C, 52.41; H, 4.39; N, 4.07.Found: C, 52.25; H, 4.36; N, 3.87.

[0252] Compound 5:3-[(3-Chloro-4-fluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid

[0253] Saponification ofN-(3-chloro-4-fluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamideas described in the preparation of compound 1 gave the title material asa white solid (99% yield). ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): mixture ofrotamers and keto-enol forms: 3.75 (3H, s), 4.88 (2H, s), 6.31 (1H, s),7.29-7.53, (3H, m).

[0254] HRMS (MAB N₂) calculated for C₁₂H₁₁ClFNO₅[M⁺]: 303.030979; Found:303.032401.

EXAMPLE 6

[0255] Compound 6-A: 3,4-Dichlorobenzaldehyde O-benzyl oxime

[0256] A solution of hydroxylamine hydrochloride (2.73 g, 39.3 mmol) inwater (35 ml) was treated with sodium acetate (2.74 g, 33.4 mmol)followed by a solution of 3,4-dichlorobenzaldehyde (4.0 g, 22.8 mmol) intetrahydrofuran (15 ml) and the resulting mixture was stirred at 22° C.for 2 h. The reaction mixture was then diluted with ether (250 ml),washed with water, brine and dried over anhydrous magnesium sulphate.Evaporation of the solvent gave 4.3 g of 3,4-dichlorobenzaldehyde oximeas a white solid.

[0257] Sodium hydride (1.05 g of 60% suspension in mineral oil, 0.63 g,26.3 mmol) was washed with hexane, suspended in tetrahydrofuran (10 ml)and then treated with benzyl bromide (2.7 ml, 22.8 mmol) A solution ofthe above oxime in tetrahydrofuran (10 ml) was then added dropwise andthe resulting mixture was stirred at 22° C. for 18 h. The reactionmixture was then diluted with dichloromethane, washed with water, brineand dried. Evaporation of the solvent and chromatography of the residueon silica gel (elution hexane-toluene, 8:2 to 1:1) gave 4.30 g (67%yield) of the title oxime ether as a clear oil. ¹HNMR 400 MHz (CDCl₃) δ(ppm) : 5.12 (2H, s, OCH₂), 7.3-7.44 (7H, m, aromatics), 7.68 (1H, d,aromatic), 8.04 (1H, s, CH).

[0258] Compound 6-B: O-Benzyl-N-(3,4-dichlorobenzyl)-hydroxylamine

[0259] Reduction of 3,4-dichlorobenzaldehyde O-benzyl oxime as describedin the preparation of compound 3-B gave the title hydroxylamine as aclear oil. The hydrochloride salt was obtained as a white solid. ¹HNMR400 MHz (DMSO-d₆) δ (ppm): 4.20 (2H, s, NCH₂), 4.83 (2H, s, OCH₂),7.3-7.45 (6H, m, aromatics), 7.63 (1H, d, J=8.2 Hz, aromatic), 7.63 (1H,s, aromatic).

[0260] Compound 6-C:N-Benzyloxy-N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-acetamide

[0261] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with O-benzyl-N-(3,4-dichlorobenzyl)-hydroxylamine as describedin the preparation of compound 1-A gave the title amide as whitecrystals (78% yield): mp 113-116° C. (ethyl acetate-hexane). ¹HNMR 400MHz (CDCl₃) δ (ppm): 1.73 (6H, s, CH₃), 4.73 (2H, s, CH₂), 4.82 (2H, s,CH₂), 6.34 (1H, s, CH), 7.18-7.41 (8H, m, aromatics). Anal. calcd forC₂₁H₁₉Cl₂NO₅: C, 57.81; H, 4.39; N, 3.21. Found: C, 57.92; H, 4.21; N,3.12.

[0262] Compound 6:3-[Benzyloxy-(3,4-dichloro-benzyl)-carbamoyl]-2-hydroxy-acrylic acid

[0263] Saponification ofN-benzyloxy-N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-acetamideas described in the preparation of compound 1 gave the title material asa white solid (91% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 4.72 (2H, s,CH₂), 4.73 (2H, s, CH₂), 6.56 (1H, s, CH), 7.12-7.52 (8H, m, aromatics).HRMS (MAB N₂) calculated for C₁₈H₁₅Cl₂NO₅ [M⁺]: 395.032728; Found:395.033590.

EXAMPLE 7

[0264] Compound 7-A: 3-Fluorobenzaldehyde O-methyloxime

[0265] Reaction of 3-fluorobenzaldehyde with methoxylamine hydrochlorideas described in the preparation of compound 3-A gave the title oximeether as a clear oil. (94% yield). HPLC indicated a 88:12 mixture of E-and Z-isomer. ¹HNMR 400 MHz (CDCl₃) δ (ppm): (E-isomer) 3.98 (3H, s,OCH₃), 7.03-7.08 (2H, m, aromatics), 7.26-7.36 (2H, m, aromatics), 8.02(1H, s, CH).

[0266] Compound 7-B: N-3-Fluorobenzyl-O-methyl-hydroxylamine

[0267] Reduction 3-fluorobenzaldehyde O-methyloxime with sodiumcyanoborohydride as described in the preparation of compound 3-B gavethe title hydroxylamine as a clear oil (60% yield). ¹HNMR 400 MHz(CDCl₃) δ (ppm): 3.50 (3H, s, OCH₃), 4.04 (2H, s, NCH₂), 5.75 (1H, broads, NH), 6.95-7.32 (4H, m, aromatics). The hydrochloride salt wasobtained as a white solid: mp 130-131° C. (dec.). Anal. calcd forC₈H₁₀FNO—HCl: C, 50.14; H, 5.78; N, 7.31. Found: C, 50.10; H, 5.73; N,7.38.

[0268] Compound 7-C:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(3-fluoro-benzyl)-N-methoxy-acetamide

[0269] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with N-(3-fluorobenzyl)-O-methyl-hydroxylamine as described inthe preparation of compound 1-A gave the title amide as a white solid(94% yield): mp 110-111° C. (ethyl acetate-hexane). ¹HNMR 400 MHz(CDCl₃) δ (ppm): 1.76 (6H, s, CH₃), 3.70 (3H, s, OCH₃), 4.82 (2H, s,NCH₂). 6.40 (1H, s, CH), 6.96-7.32 (4H, m, aromatics). Anal. calcd. forC₁₅H₁₆FNO₅: C, 58.25; H, 5.21; N, 4.52. Found: C, 58.00; H, 5.30; N,4.49.

[0270] Compound 7:3[(3-Fluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid

[0271] Saponification of2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide asdescribed in the preparation of compound 1 gave the title material as awhite solid (97% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.73 (3H, s,OCH₃), 4.84 (2H, s, NCH₂), 6.57 (1H, s, CH), 7.0-7.35 (4H, m,aromatics). HRMS calcd. For C₁₂H₁₂FNO₅ [M⁺]: 269.069951. Found:269.070091.

EXAMPLE 8

[0272] Compound 8-A: 2-Fluorobenzaldehyde O-methyloxime

[0273] Reaction of 2-fluorobenzaldehyde with methoxylamine hydrochlorideas described in the preparation of compound 3-A gave the title oximeether as a clear oil (98% yield). HPLC indicated a 91:9 mixture of E-and Z-isomers. ¹HNMR 400 MHz (CDCl₃) δ (ppm): (E-isomer) 3.99 (3H, s,OCH₃), 7.07 (1H, m, aromatic), 7.14 (1H, m, aromatic), 7.34 (1H, m,aromatic), 7.82 (1H, m, aromatic), 8.31 (1H, s, CH).

[0274] Compound 8-B: N-2-Fluorobenzyl-O-methyl-hydroxylamine

[0275] Reduction of 2-fluorobenzaldehyde O-methyloxime with sodiumcyanoborohydride as described in the preparation of compound 3-B gavethe title hydroxylamine as a clear oil (74% yield). ¹HNMR 400 MHz(CDCl₃) δ (ppm): 3.52 (3H, s, OCH₃), 4.11 (2H, s, NCH₂), 5.78 (1H, broads, NH), 7.05 (1H, m, aromatic), 7.11 (1H, m, aromatic), 7.27 (1H, m,aromatic), 7.38 (1H, m, aromatic). The hydrochloride salt was obtainedas a white solid: mp 138-143° C. (dec.). Anal. calcd. for C₈H₁₀FNO—HCl:C, 50.14; H, 5.78; N, 7.31. Found: C, 50.37; H, 5.71; N, 7.18.

[0276] Compound 8-C:2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-(2-fluoro-benzyl)-N-methoxyacetamide

[0277] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with N-(2-fluorobenzyl)-O-methyl-hydroxylamine as described inthe preparation of compound 1-A gave the title amide as a white solid(84% yield): mp 109-111° C. (ethyl acetate-hexane). ¹HNMR 400 MHz(CDCl₃) δ (ppm): 1.75 (6H, s, CH₃), 3.72 (3H, s, OCH₃), 4.92 (2H, s,NCH₂), 6.40 (1H, s, CH), 7.03-7.12 (2H, m, aromatics), 7.24-7.30 (1H, m,aromatic), 7.4 (1H, m, aromatic). Anal. calcd. for C₁₅H₁₆FNO₅: C, 58.25;H, 5.21; N, 4.52. Found: C, 58.47; H, 5.16; N, 4.66.

[0278] Compound 8:3-[(2-Fluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid

[0279] Saponification of2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-(2-fluoro-benzyl)-N-methoxyacetamide as described in the preparation of compound 1 gave the titlematerial as white crystals (60% yield).

[0280]¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.73 (3H, s, OCH₃), 4.84 (2H, s,NCH₂), 6.57 (1H, s, CH), 7.0-7.35 (4H, m, aromatics). HRMS (MAB N₂)calculated for C₁₂H₁₂FNO₅ [M⁺]269.069951: Found: 269.070089.

EXAMPLE 9

[0281] Compound 9-A: 4-Fluorophenylacetaldehyde O-methyloxime

[0282] Reaction of 4-fluorophenylacetaldehyde with methoxylaminehydrochloride as described in the preparation of compound 3-A gave thetitle oxime ether as a clear oil (43% yield). ¹HNMR indicated a 1:1mixture of E- and Z-isomers. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.51 (2H, d,J=6.7 Hz, CH₂), 3.66 (2H, d, J=5.5 Hz, CH₂), 3.88 (3H, s, OCH₃), 3.96(3H H, s, OCH₃), 6.79 (1H, t, J=5.5 Hz, CH), 7.03 (2H, m, aromatics),7.19 (2H, m, aromatics), 7.45 (1H, t, J=6.7 Hz, CH).

[0283] Compound 9-B: N-[2-(4-Fluorophenyl)-ethyl]-O-methyl-hydroxylamine

[0284] Reduction of 4-fluorophenylacetaldehyde O-methyloxime with sodiumcyanoborohydride as described in the preparation of compound 3-B gavethe title hydroxylamine as a clear oil after chromatography on silicagel (62% yield). ¹HNMR 400 MHz (C₆D₆) δ (ppm): 2.64 (2H, t, J=7.1 Hz,CH₂), 2.97 (2H, t, J=7.1 Hz, CH₂), 3.53 (3H, s, OCH₃), 5.24 (broad, NH),6.9 (4H, m, aromatics).

[0285] Compound 9-C:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-[2-(4-fluoro-phenyl)-ethyl]-N-methoxy-acetamide

[0286] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with N-[2-(4-fluorophenyl)-ethyl]-O-methyl-hydroxylamine asdescribed in the preparation of compound 1-A gave the title amide aswhite crystals (86% yield): mp 106-107° C. (ethyl acetate-hexane). ¹HNMR400 MHz (CDCl₃) δ (ppm): 1.76 (6H, s, CH₃), 2.95 (2H, m, CH₂), 3.72 (3H,s, OCH₃), 3.87 (2H, m, NCH₂), 6.38 (1H, broad s, CH), 6.99 (2H, m,aromatics), 7.20 (2H, m, aromatics). Anal. calcd for C₁₆H₁₈FNO₅: C,59.43; H, 5.61; N, 4.33. Found: C, 59.39; H, 5.43; N, 4.13.

[0287] Compound 9:3-{[2-(4-Fluoro-phenyl)-ethyl]-methoxy-carbamoyl}-2-hydroxy-acrylic acid

[0288] Saponification of2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-[2-(4-fluoro-phenyl)-ethyl]-N-methoxy-acetamideas described in the preparation of compound 1 gave the title material aswhite crystals (92% yield): mp 107-108° C. (dec) (ethyl acetate-hexane).¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 2.88 (2H, t, J=7.1 Hz, CH₂), 3.72 (3H,s, OCH₃), 3.90 (2H, t, J=7.1 Hz, NCH₂), 6.25 (1H, s, CH), 7.11 (2H, m,aromatics), 7.28 (2H, m, aromatics), 13.27 (1H, broad, OH), 13.75 (1H,broad, OH). Anal. calcd for C₁₃H₁₄FNO₅: C, 55.12; H, 4.98; N, 4.94.Found: C, 55.05; H, 4.85; N, 4.91.

EXAMPLE 10

[0289] Compound 10-A:N-(4-Chloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide

[0290] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with N-(4-chlorobenzyl)-O-methyl-hydroxylamine (Kawase, M.;Kikugawa, Y. J. Chem. Soc. Perkin Trans.1, 1979, 643-645) as describedin the preparation of compound 1-A gave the title amide as whitecrystals (95% yield): mp 129-130° C. (ethyl acetate-hexane). ¹HNMR 400MHz (CDCl₃) δ (ppm): 1.75 (6H, s, CH₃), 3.69 (3H, s, OCH₃), 4.79 (2H, s,NCH₂), 6.39 (1H, s, CH), 7.4 (4H, s, aromatics). Anal. calcd. forC₁₅H₁₆ClNO₅: C, 55.31; H, 4.95; N, 4.30. Found: C, 55.32; H, 4.95; N,4.27.

[0291] Compound 10:3-[(4-Chloro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid

[0292] Saponification ofN-(4-chloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamideas described in the preparation of compound 1 gave the title material aswhite crystals (74% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.71 (3H, s,OCH₃), 4.81 (2H, s, NCH₂), 6.55 (1H, s, CH), 7.26-7.34 (4H, m,aromatics). HRMS (MAB N₂) calculated for C₁₂H₁₂ClNO₅[M⁺]: 285.040400;Found: 285.039996.

EXAMPLE 11

[0293] Compound 11-A: 3,4-Difluorobenzaldehyde O-methyloxime

[0294] Reaction of 3,4-difluorobenzaldehyde with methoxylaminehydrochloride as described in the preparation of compound 3-A gave thetitle oxime ether as a clear oil (100% yield). ¹HNMR indicated a 85:15mixture of E- and Z-isomers. ¹HNMR 400 MHz (CDCl₃) δ (ppm): (E-isomer)3.97 (3H, s, OCH₃), 7.12-7.26 (2H, m, aromatics), 7.44-7.52 (1H, m,aromatic), 7.97 (1H, s, CH).

[0295] Compound 11-B: N-3,4-Difluorobenzyl-O-methyl-hydroxylamine

[0296] Reduction of 3,4-difluorobenzaldehyde O-methyloxime with sodiumcyanoborohydride as described in the preparation of compound 3-B gavethe title hydroxylamine as a clear oil (82% yield). ¹HNMR 400 MHz(CDCl₃) δ (ppm): 3.48 (3H, s, OCH₃), 3.98 (2H, s, NCH₂), 5.73 (1H, broads, NH), 7.04-7.23 (3H, m, aromatics). The hydrochloride salt wasobtained as a white solid: mp 139-142° C. (dec.). Anal. calcd. forC₈H₉F₂NO₂—HCl: C, 45.83; H. 4.80; N, 6.68. Found: C, 45.96; H, 4.93, N,6.67.

[0297] Compound 11-C:N-(3,4-Difluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide

[0298] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with N-3,4-difluorobenzyl-O-methyl-hydroxylamine as describedin the preparation of compound 1-A gave the title amide as a white solid(96% yield): mp 110-111° C. (ethyl acetate-hexane). ¹HNMR 400 MHz(CDCl₃) δ (ppm): 1.76 (6H, s, CH₃), 3.71 (3H, s, OCH₃), 4.72 (2H, s,NCH₂), 6.38 (1H, s, CH), 7.05-7.22 (3H, m, aromatics). Anal. calcd. forC₁₅H₁₅NO₅: C, 55.04; H, 4.62; N, 4.28. Found: C, 54.99; H, 4.55; N,4.22.

[0299] Compound 11:3-[(3,4-Difluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid

[0300] Saponification ofN-(3,4-difluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamideas described in the preparation of compound 1 gave the title material aswhite crystals (95% yield): mp 127-129° C. (ethyl acetate-hexane). ¹HNMR400 MHz (CDCl₃) δ (ppm): 3.73 (3H, s, OCH₃), 4.78.(2H, s, NCH₂), 6.55(1H, s, CH), 7.04-7.19 (3H, m, aromatics). Anal. calcd. for C₁₂H₁₁F₂NO₅:C, 50.18; H, 3.86; N, 4.88. Found: C, 49.98; H, 3.91; N, 4.64.

EXAMPLE 12

[0301] Compound 12-A: 4-Fluorobenzaldehyde O-ethyloxime

[0302] Reaction of 4-fluorobenzaldehyde with ethoxylamine hydrochlorideas described in the preparation of compound 3-A gave the title oximeether as a clear oil after chromatography on silica gel (elutiontoluene-ethyl acetate 95:5) and distillation (58% yield). ¹HNMR 400 MHz(CDCl₃) δ (ppm): 1.35 (3H, t, J=7.07 Hz, CH₃), 4.24 (2H, q, J=7.07 Hz,OCH₂), 7.08 (2H, m, aromatics), 7.59 (2H, m, aromatics), 8.07 (1H, s,CH).

[0303] Compound 12-B: O-Ethyl-N-4-fluorobenzyl-hydroxylamine

[0304] Reduction of 4-fluorobenzaldehyde O-ethyloxime with sodiumcyanoborohydride as described in the preparation of compound 3-B gavethe title hydroxylamine as a clear oil after chromatography (74% yield).¹HNMR 400 MHz (C₆D₆) δ (ppm): 1.13 (3H, t, J=7.1 Hz, CH₃), 3.70 (2H, q,J=7.1 Hz, OCH₂), 3.78 (2H, d, J=5.4 Hz, NCH₂), 5.20 (2H, broad t, NH),6.89 (2H, m, aromatics), 7.09 (2H, m, aromatics). Anal. calcd forC₉H₁₂FNO: C, 63.88; H, 7.14; N, 8.27. Found: C, 63.68; H, 7.08; N, 8.46.

[0305] Compound 12-C:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-ethoxy-N-(4-fluoro-benzyl)-acetamide

[0306] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with O-ethyl-N-4-fluorobenzyl-hydroxylamine as described in thepreparation of compound 1-A gave the title amide as white crystals (92%yield): mp 95-96° C. (ethyl acetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ(ppm): 1.27 (3H, t, J=7.07 Hz, CH₃), 1.77 (6H, s, CH₃), 3.90 (2H, q,J=7.07 Hz, OCH₂), 4.81 (2H, s, NCH₂), 6.41 (1H, s, CH), 7.03 (2H, m,aromatics), 7.37 (2H, m, aromatics). Anal. calcd for C₁₆H₁₈FNO₅: C,59.43; H, 5.61; N, 4.33. Found: C, 59.50; H, 5.60; N, 4.17.

[0307] Compound 12:3-[Ethoxy-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic acid

[0308] Saponification of2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-ethoxy-N-(4-fluorobenzyl)-acetamideas described in the preparation of compound 1 gave the title material aswhite crystals (96% yield): mp 120-121° C. (dec.), (ethylacetate-hexane). ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): (mixture of enol andketo forms, 78: 22); enol form: 1.18 (3H, t, J=7.0 Hz, CH₃), 3.98 (2H,t, J=7.0 Hz, OCH₂), 4.87 (2H, s, NCH₂), 6.32 (1H, s, CH), 7.19 (2H, m,aromatics), 7.36 (2H, m, aromatics), 13.3 (1H, broad s, OH), 13.8 (1H,broad s, OH). Anal. calcd for C₁₃H₁₄FNO₅: C, 55.12; H, 4.98; N, 4.94.Found: C, 54.96; H, 4.80; N, 4.88.

EXAMPLE 13

[0309] Compound 13-A: 4-Fluorobenzaldehyde O-isobutyloxime

[0310] Reaction of 4-fluorobenzaldehyde with O-isobutyl-hydroxylaminehydrochloride as described in the preparation of compound 3-A gave thetitle oxime ether as a clear oil after chromatography on silica gel(elution toluene-ethyl acetate 95:5), (77% yield). ¹HNMR 400 MHz (CDCl₃)δ (ppm): 0.98 (6H, d, J=6.5 Hz, CH₃), 2.07 (1H, m, CH), 3.95 (2H, d,J=7.18 Hz, OCH₂), 7.08 (2H, m, aromatics), 7.59 (2H, m, aromatics), 8.08(1H, s, CH). Anal. calcd for C₁₁H₁₄FNO: C, 67.67; H, 7.22; N, 7.17.Found: C, 67.71; H, 7.32; N, 7.38.

[0311] Compound 13-B: N-(4-Fluorobenzyl)-O-isobutyl-hydroxylamine

[0312] Reduction of 4-fluorobenzaldehyde O-isobutyloxime with sodiumcyanoborohydride as described in the preparation of compound 3-B gavethe title hydroxylamine as a clear oil after chromatography (65% yield).

[0313]¹HNMR 400 MHz (C₆D₆) δ (ppm): 0.87 (6H, d, J=6.75 Hz, CH₃), 1.88(1H, m, CH), 3.46 (2H, d, J=6.41 Hz, OCH₂), 4.05 (2H, s, NCH₂), 7.04(2H, m, aromatics), 7.37 (2H, m, aromatics). Anal. calcd for C₁₁H₁₆FNO:C, 66.98; H, 8.17; N, 7.10. Found: C, 66.88; H, 7.97; N, 7.32.

[0314] Compound 13-C:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-isobutoxy-acetamide

[0315] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with N-(4-fluorobenzyl)-O-isobutyl-hydroxylamine as describedin the preparation of compound 1-A gave the title amide as whitecrystals (91% yield): mp 105-106° C. (ethyl acetate-hexane). ¹HNMR 400MHz (CDCl₃) δ (ppm): 0.98 (3H, d, J=6.45 Hz, CH₃), 1.77 (6H, s, CH₃),1.95 (1H, m, CH), 3.64 (2H, d, J=6.63 Hz, OCH₂), 4.80 (2H, s, NCH₂),6.41 (1H, s, CH), 7.03 (2H, m, aromatics), 7.36 (2H, m, aromatics).Anal. calcd for C₁₈H₂₂FNO₅: C, 61.53; H, 6.31; H, 3.98. Found: C, 61.47;H, 6.39; N, 3.97.

[0316] Compound 13:3-[(4-Fluoro-benzyl)-isobutoxy-carbamoyl]-2-hydroxy-acrylic acid

[0317] Saponification of2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluorobenzyl)-N-isobutoxy-acetamideas described in the preparation of compound 1 gave the title material aswhite crystals (96% yield): mp 100-101° C., (ethyl acetate-hexane).¹HNMR 400 MHz (DMSO-d₆) δ (ppm): (mixture of enol and keto forms, 8:2);enol form: 0.91 (3H, d, J=6.49 Hz, CH₃), 1.47 (1H, m, CH), 3.74 (2H, d,J=5.84 Hz, OCH₂), 4.86 (2H, s, NCH₂), 6.35 (1H, s, CH), 7.18 (2H, m,aromatics), 7.36 (2H, m, aromatics), 13.2 (1H, broad s, OH). Anal. calcdfor C₁₅H₁₈FNO₅: C, 57.87; H, 5.82; N, 4.50. Found: C, 57.88; H, 5.84; N,4.30.

EXAMPLE 14

[0318] Compound 14-A: 3-Bromo-4-fluorobenzaldehyde O-methyloxime

[0319] Reaction of 3-bromo-4-fluorobenzaldehyde with methoxylaminehydrochloride as described in the preparation of compound 3-A gave thetitle oxime ether as a clear oil (95% yield). ¹HNMR indicated a 95:5mixture of E- and Z-isomers. ¹HNMR 400 MHz (CDCl₃) δ (ppm): (E-isomer)3.97 (3H, s, OCH₃), 7.12 (1H, m, aromatics), 7.48 (1H, m, aromatic),7.82 (1H, m, aromatic), 7.97 (1H, s, CH).

[0320] Compound 14-B: N-3-Bromo-4-fluorobenzyl-O-methyl-hydroxylamine

[0321] Reduction of 3-bromo-4-fluorobenzaldehyde O-methyloxime withsodium cyanoborohydride as described in the preparation of compound 3-Bgave the title hydroxylamine as a clear oil (83% yield). ¹HNMR 400 MHz(CDCl₃) δ (ppm): 3.48 (3H, s, OCH₃), 3.99 (2H, s, NCH₂), 7.08 (1H, m,aromatic), 7.27 (1H, m, aromatic), 7.57 (1H, m, aromatic). Thehydrochloride salt was obtained as a white solid: mp 150-151° C. Anal.calcd. for C₈H₉BrFNO—HCl: C, 35.52; H, 3.73; N, 5.18. Found: C, 35.54;H, 3.61; N, 5.12.

[0322] Compound 14-C:N-(3-Bromo-4-fluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide

[0323] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with N-3-bromo-4-fluorobenzyl-O-methyl-hydroxylamine asdescribed in the preparation of compound 1-A gave the title amide as awhite solid (100% yield): mp 117-119° C. (ethyl acetate-hexane). ¹HNMR400 MHz (CDCl₃) δ (ppm): 1.75 (6H, s, CH₃), 3.71 (3H, s, OCH₃), 4.76(2H, s, NCH₂), 6.38 (1H, s, CH), 7.07 (1H, m, aromatic), 7.28 (1H, m,aromatic), 7.56 (1H, m, aromatic). Anal. calcd. for C₁₅H₁₅BrFNO₅: C,46.41; H, 3.89; N, 3.61. Found: C, 46.43; H, 4.01; N, 3.53.

[0324] Compound 14:3-[(3-Bromo-4-fluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid

[0325] Saponification ofN-(3-bromo-4-fluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamideas described in the preparation of compound 1 gave the title material aswhite crystals (88% yield): mp 140-141° C. (ethyl acetate-hexane). ¹HNMR400 MHz (CDCl₃) δ (ppm): 3.74 (3H, s, OCH₃), 4.78 (2H, s, NCH₂), 6.56(1H, s, CH), 7.10 (1H, m, aromatic), 7.26 (1H, m, aromatic), 7.53 (1H,m, aromatic). Anal. calcd. for C₁₂H₁₁BrFNO₅: C, 41.40; H, 3.18; N, 4.02.Found: C, 41.53; H, 3.26; N, 3.94.

EXAMPLE 15

[0326] Compound 15-A: 2-Methylbenzaldehyde O-methyloxime

[0327] Reaction of 2-methylbenzaldehyde with methoxylamine hydrochlorideas described in the preparation of compound 3-A gave the title oximeether as a clear oil (96% yield). HPLC indicated a 95:5 mixture of E-and Z-isomers. ¹HNMR 400 MHz (CDCl₃) δ (ppm): (E-isomer) 2.44 (3H, s,CH₃), 4.01 (3H, s, OCH₃), 7.19-7.28 (3H, m, aromatics), 7.73 (1H, m,aromatic), 8.36 (1H, s, CH).

[0328] Compound 15-B: N-2-Methylbenzyl-O-methyl-hydroxylamine

[0329] Reduction of 2-methylbenzaldehyde O-methyloxime with sodiumcyanoborohydride as described in the preparation of compound 3-B gavethe title hydroxylamine as a clear oil (83% yield). ¹HNMR 400 MHz(CDCl₃) δ (ppm): 2.42 (3H, s, CH₃), 3.55 (3H, s, OCH₃), 4.11 (2H, s,NCH₂), 5.64 (1H, s, NH), 7.19-7.32 (4H, m, aromatics). The hydrochloridesalt was obtained as a white solid: mp 148-150° C. Anal. calcd. forC₉H₁₃NO—HCl: C, 57.60; H, 7.51; N, 7.46. Found: C, 57.59; H, 7.69; N,7.52.

[0330] Compound 15-C:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-N-(2-methyl-benzyl)-acetamide

[0331] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with N-(2-methylbenzyl)-O-methyl-hydroxylamine as described inthe preparation of compound 1-A gave the title amide as white crystals(100% yield): mp 96-97° C. (ethyl acetate-hexane). ¹HNMR 400 MHz (CDCl₃)δ (ppm): 1.78 (6H, s, CH₃), 2.4 (3H, s, Ce), 3.59 (3H, s, OCH₃), 4.89(2H, s, NCH₂), 6.44 (1H, s, CH), 7.2-7.28 (4H, m, aromatics). Anal.calcd. for C₁₆H₁₉NO₅: C, 62.94; H, 6.27; N, 4.59. Found: C, 62.90; H,6.21; N, 4.52.

[0332] Compound 15:2-Hydroxy-3-[methoxy-(2-methyl-benzyl)-carbamoyl]-acrylic acid

[0333] Saponification of2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-N-(2-methyl-benzyl)-acetamideas described in the preparation of compound 1 gave the title material aswhite crystals (100% yield): mp 85-87° C. (dec.)(ethyl acetate-hexane).¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.39 (3H, s, CH₃), 3.63 (3H, s, OCH₃),4.9 (2H, s, NCH₂), 6.6 (1H, s, CH), 7.22-7.28 (4H, m, aromatics). Anal.calcd. for C₁₃H₁₅NO₅: C, 58.86; H, 5.70; N, 5.28. Found: C, 58.59; H,5.67; N, 5.14.

EXAMPLE 16

[0334] Compound 16-A: 4-Methoxybenzaldehyde O-methyloxime

[0335] Reaction of 4-methoxybenzaldehyde with methoxylaminehydrochloride as described in the preparation of compound 3-A gave thetitle oxime ether as a clear oil (100% yield ). ¹HNMR indicated a 95:5mixture of E- and Z-isomers. ¹HNMR 400 MHz (CDCl₃) δ (ppm): (E-isomer)3.83 (3H, s, OCH₃), 3.94 (3H, s, OCH₃), 6.89 (2H, m, aromatics), 7.52(2H, m, aromatics), 8.05 (1H, s, CH).

[0336] Compound 16-B: N-4-Methoxybenzyl-O-methyl-hydroxylamine

[0337] Reduction of 4-methoxybenzaldehyde O-methyloxime with sodiumcyanoborohydride as described in the preparation of compound 3-B gavethe title hydroxylamine as a clear oil (96% yield). ¹HNMR 400 MHz(CDCl₃) δ (ppm): 3.49 (3H, s, OCH₃), 3.79 (3H, s, OCH₃), 3.98 (2H, s,NCH₂), 5.62 (1H, broad s, NH), 6.86 (2H, m, aromatics), 7.25 (2H, m,aromatics). The hydrochloride salt was obtained as a white solid: mp157-158° C. (dec.). Anal. calcd. for C₉H₁₃NO₂—HCl: C, 53.03; H, 6.92; N,6.87. Found: C, 53.14; H, 6.76; N, 6.80.

[0338] Compound 16-C:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-N-(4-methoxy-benzyl)-acetamide

[0339] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with N-(4-methoxybenzyl)-O-methyl-hydroxylamine as described inthe preparation of compound 1-A gave the title amide as white crystals(97% yield): mp 113-114° C. (ethyl acetate-hexane). ¹HNMR 400 MHz(CDCl₃) δ (ppm): 1.75 (6H, s, CH₃), 3.66 (3H, s, OCH₃), 3.79 (3H, s,OCH₃), 4.77 (2H, s, NCH₂), 6.38 (1H, s, CH), 6.85 (2H, m, aromatics),7.29 (2H, m, aromatics). Anal. calcd. for C₁₆H₁₉NO₆: C, 59.80; H, 5.96;N, 4.35. Found: C, 59.87; H, 5.76; N, 4.17.

[0340] Compound 16:2-Hydroxy-3-[methoxy-(4-methoxy-benzyl)-carbamoyl]-acrylic acid

[0341] Saponification of2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-N-(4-methoxy-benzyl)-acetamideas described in the preparation of compound 1 gave the title material aswhite crystals (95% yield): mp 83-86° C. (ethyl acetate-hexane). ¹HNMR400 MHz (CDCl₃) δ (ppm): 3.69 (3H, s, OCH₃), 3.80 (3H, s, OCH₃), 4.78(2H, s, NCH₂), 6.54 (1H, s, CH), 6.88 (2H, m, aromatics), 7.27 (2H, m,aromatics). Anal. calcd. for C₁₃H₁₅NO₆: C, 55.51; H, 5.37; N, 4.98.Found: C, 55.45; H, 5.31; N, 4.79.

EXAMPLE 17

[0342] Compound 17-A: 2,4-Difluorobenzaldehyde O-methyloxime

[0343] Reaction of 2,4-difluorobenzaldehyde with methoxylaminehydrochloride as described in the preparation of compound 3-A gave thetitle oxime ether as a clear oil (80% yield). ¹HNMR indicated a 95:5mixture of E- and Z-isomers. ¹HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer)3.98 (3H, s, OCH₃), 6.79-6.91 (2H, m, aromatics), 7.79-7.85 (1H, m,aromatic), 8.24 (1H, s, CH).

[0344] Compound 17-B: N-2,4-Difluorobenzyl-O-methyl-hydroxylamine

[0345] Reduction of 2,4-difluorobenzaldehyde O-methyloxime with sodiumcyanoborohydride as described in the preparation of compound 3-B gavethe title hydroxylamine as a clear oil (72% yield). ¹HNMR 400 MHz(CDCl₃) δ (ppm): 3.51 (3H, s, OCH₃), 4.07 (2H, s, NCH₂), 6.78-6.88 (2H,m, aromatics), 7.32-7.38 (1H, m, aromatic). The hydrochloride salt wasobtained as a white solid: mp 154-158° C. (dec.). Anal. calcd. forC₈H₉NO₂—HCl: C, 45.83; H, 4.80; N, 6.68. Found: C, 45.81; H, 4.84; N,6.59.

[0346] Compound 17-C:N-(2,4-Difluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide

[0347] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with N-2,4-difluorobenzyl-O-methyl-hydroxylamine as describedin the preparation of compound 1-A gave the title amide as a white solid(97% yield): mp 120-125° C. (ethyl acetate-hexane). ¹HNMR 400 MHz(CDCl₃) δ (ppm): 1.75 (6H, s, CH₃), 3.73 (3H, s, OCH₃), 4.86 (2H, s,NCH₂), 6.38 (1H, s, CH), 6.78-6.87 (2H, m, aromatics), 7.37-7.43 (1H, m,aromatic). Anal. calcd. for C₁₅H₁₅F₂NO₅: C, 55.04; H, 4.62; N, 4.28.Found: C, 55.03; H. 4.43; N, 4.17.

[0348] Compound 17:3-[(2,4-Difluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid

[0349] Saponification ofN-(2,4-difluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamideas described in the preparation of compound 1 gave the title material aswhite crystals (100% yield): mp 131-132° C. (ethyl acetate-hexane).¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.74 (3H, s, OCH₃), 4.88 (2H, s, NCH₂),6.55 (1H, s, CH), 6.81-6.90 (2H, m, aromatics), 7.31-7.37 (1H, m,aromatic). Anal. calcd. for C₁₂H₁₁F₂NO₅: C, 50.18; H, 3.86; N, 4.88.Found: C, 50.19; H, 3.87; N, 4.83.

EXAMPLE 18

[0350] Compound 18-A: 4-Carbomethoxybenzaldehyde O-methyloxime

[0351] Reaction of methyl 4-formylbenzoate with methoxylaminehydrochloride as described in the preparation of compound 3-A gave thetitle oxime ether (96% yield) as a white solid (mixture of E- andZ-isomers). The E-isomer was obtained as white crystals from hexane; mp66-67° C. (Lit. mp 65-66° C., Cooks, R. G.; Varvoglis, A. G. Org. MassSpectrum., 5, 1971, 687). ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): (E-isomer)3.86 (3H, s, OCH₃), 3.93 (3H, s, OCH₃), 7.75 (2H, d, aromatics), 7.98(2H, d, aromatics), 8.32 (1H, s, CH).

[0352] Compound 18-B: N-4-Carbomethoxybenzyl-O-methyl-hydroxylamine

[0353] Reduction of 4-carbomethoxybenzaldehyde O-methyloxime with sodiumcyanoborohydride as described in the preparation of compound 3-B gavethe title hydroxylamine as an oil (53% yield). The hydrochloride saltwas obtained as a white solid: mp 166-169° C. ¹HNMR 400 MHz (DMSO-d₆) δ(ppm): 3.75 (3H, s, OCH₃), 3.86 (3H, s, OCH₃), 4.39 (2H, s, NCH₂), 7.65(2H, d, aromatics), 7.97 (2H, d, aromatics). Anal. calcd forC₁₀H₁₃NO₃—HCl: C, 51.84; H, 6.09; N, 6.04. Found: C, 51.74; H, 6.01; N,5.50.

[0354] Compound 18-C:4-({[2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl]-methoxy-amino}-methyl)benzoicacid methyl ester

[0355] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with N-4-carbomethoxybenzyl-O-methyl-hydroxylamine as describedin the preparation of compound 1-A gave the title amide as a white solid(83% yield): mp 120° C. (dichloromethane-hexane). ¹HNMR 400 MHz (CDCl₃)δ (ppm): 1.75 (6H, s, CH₃), 3.67 (3H, s, OCH₃), 3.91 (3H, s, OCH₃), 4.88(2H, s, NCH₂), 6.40 (1H, s, CH), 7.42 (2H, d, aromatics), 8.0 (2H, d,aromatics). Anal. calcd for C₁₇H₁₉NO₇: C, 58.45; H, 5.48; N, 4.01.

[0356] Found: C, 58.54; H, 5.55; N, 3.61.

[0357] Compound 18:4-{[(3-Carboxy-3-hydroxy-acryloyl)-methoxy-amino]-methyl}-benzoic acidmethyl ester

[0358] Saponification of4-({[2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl]-methoxy-amino}-methyl)benzoicacid methyl ester as described in the preparation of compound 1 gave thetitle material as white crystals (72% yield): mp 110-111° C.(dichloromethane-hexane).

[0359]¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.72 (3H, s, OCFB), 3.92 (3H, s,OCH₃), 4.90 (2H, s, NCH₂), 6.58 (1H, s, CH),. 7.39 (2H, d, aromatics),8.02 (2H, d, aromatics). Anal. calcd for C₁₄H₁₅NO₇: C, 53.74; H, 4.96;H, 4.48. Found: C, 53.61; H, 4.78; N, 4.44.

EXAMPLE 19

[0360] Compound 19-A: 3-Cyano-4-fluorobenzaldehyde O-methyloxime

[0361] Reaction of 3-cyano-4-fluorobenzaldehyde with methoxylaminehydrochloride as described in the preparation of compound 3-A gave thetitle oxime ether as a clear oil after chromatography on silica gel(elution hexane-ethyl acetate 8:2) (94% yield). ¹HNMR indicated a 93:7mixture of E- and Z-isomers. ¹HNMR 400 MHz (CDCl₃) δ (ppm): (E-isomer)4.02 (3H, s, OCH₃), 7.26 (1H, m, aromatic), 7.85 (2H, m, aromatics),8.03 (1H, s, CH).

[0362] Compound 19-B: N-(3-Cyano-4-fluorobenzyl)-O-methyl-hydroxylamine

[0363] Reduction of 3-cyano-4-fluorobenzaldehyde O-methyloxime withsodium cyanoborohydride as described in the preparation of compound 3-Bgave the title hydroxylamine as a clear oil after chromatography onsilica gel (elution hexane-ethyl acetate 8: 2) (73% yield). ¹HNMR 400MHz (CDCl₃) δ (ppm): 3.46 (3H, s, OCH₃), 4.02 (2H, s, NCH₂), 7.18 (1H,t, aromatic), 7.58-7.66 (2H, m, aromatics). The hydrochloride salt wasobtained as a white solid: mp 152-158° C. Anal. calcd for C₉H₉FN₂O—HCl:C, 49.89; H, 4.65; N, 12.93. Found: C, 50.04; H, 4.64; N, 12.84.

[0364] Compound 19-C:N-(3-Cyano-4-fluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide

[0365] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with N-(3-cyano-4-fluorobenzyl)-O-methyl-hydroxylamine asdescribed in the preparation of compound 1-A gave the title amide aswhite crystals (97% yield): mp 119-120° C. (ethyl acetate-hexane). ¹HNMR400 MHz (CDCl₃) δ (ppm): 1.75 (6H, s, CH₃), 3.75 (3H, s, OCH₃), 4.78(2H, s, NCH₂), 6.36 (1H, s, CH), 7.17 (1H, t, aromatic), 7.58-7.64 (2H,m, aromatics). Anal. calcd for C₁₆H₁₅F₂NO₅: C, 57.48; H, 4.52; N, 8.38.Found: C, 57.39; H, 4.61; N, 8.32.

[0366] Compound 19:3-[(3-Cyano-4-fluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid

[0367] Saponification ofN-(3-cyano-4-fluorobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamideas described in the preparation of compound 1 gave the title material aswhite crystals (93% yield): mp 144-151° C. (dec) (ethyl acetate-hexane).¹HNMR 400 MHz (DMSO-d₆) δ (ppm): (mixture of enol and keto forms, 7:3);enol form: 3.75 (3H, s, OCH₃), 4.92 (2H, s, NCH₂), 6.31 (1H, s, CH),7.53 (1H, m, aromatic), 7.68-7.87 (2H, m, aromatics). Anal. calcd for:C₁₃H₁₁FN₂O₅: C, 53.07; H, 3.77; N, 9.52. Found: C, 52.93; H, 3.85; N,9.45.

EXAMPLE 20

[0368] Compound 20-A: (4-Fluorobenzylideneaminooxy)-acetic acidtert-butyl ester

[0369] Condensation of 4-fluorobenzaldehyde with hydroxylaminehydrochloride followed by reaction with tert-butyl bromoacetate usingthe same procedure as described for compound 6-A gave the title oximeether as a clear oil (84% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.52(9H, s, t-Bu), 4.61 (2H, s, OCH₂), 7.08 (2H, m, aromatics), 7.59 (2H, m,aromatics), 8.19 (1H, s, CH).

[0370] Compound 20-B: [N-(4-Fluorobenzyl)aminooxy]-acetic acidtert-butyl ester

[0371] Reduction of (4-fluorobenzylideneaminooxy)-acetic acid tert-butylester as described in the preparation of compound 3-B gave the titlehydroxylamine as a clear oil (65% yield). ¹HNMR 400 MHz (C₆D₆) δ (ppm):1.43 (9H, s, t-Bu), 3.84 (2H, d, J=5.6 Hz, NCH₂), 4.17 (2H, s, OCH₂),6.39 (1H, broad t, NH), 6.86 (2H, m, aromatics), 7.05 (2H, m,aromatics).

[0372] Compound 20-C:[[2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl]-(4-fluoro-benzyl)-aminooxy]-aceticacid tert-butyl ester

[0373] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with [N-(4-fluorobenzyl)aminooxy]-acetic acid tert-butyl esteras described in the preparation of compound 1-A gave the title amide aswhite crystals (85% yield): mp 119-120° C. (ethyl acetate-hexane). 1HNMR400 MHz (CDCl₃) δ (ppm): 1.48 (9H, s, t-Bu), 1.74 (6H, s, CH₃), 4.30(2H, s, CH₂), 4.88 (2H, s, CH₂), 6.48 (1H, s, CH), 7.0 (2H, m,aromatics), 7.38 (2H, m, aromatics). Anal. calcd for C₂₀H₂₄FNO₇: C,58.67; H, 5.91; N, 3.42.

[0374] Found: C, 58.83; H, 5.92; N, 3.31.

[0375] Compound 20:3-[tert-Butoxycarbonylmethoxy-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylicacid

[0376] A solution of[[2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-acetyl]-(4-fluorobenzyl)-aminooxy]-aceticacid tert-butyl ester (0.10 g, 0.24 mmol) in tetrahydrofuran (3 ml) wastreated at 0° C. with 0.48 ml (0.48 mmol) of 1 M aqueous lithiumhydroxide. After 1 h, the reaction mixture was acidified with 1Nhydrochloric acid and extracted with ethyl acetate. The organic phasewas washed with brine, dried (magnesium sulphate) and evaporated invacuo. Chromatograpy of the residual solid on Premisphere 5 μC-8(gradient of acetonitrile in water) gave 0.037 g (41% yield) of thetitle material as a white solid: mp 73° C. (dec). ¹HNMR 400 MHz (CDCl₃)δ (ppm): 1.51 (9H, s t-Bu), 4.36 (2H, s, CH₂), 4.95 (2H, s, CH₂), 6.66(1H, broad s, CH), 7.05 (2H, m, aromatics), 7.39 (2H, m, aromatics).HRMS (ES⁺) calculated for C₁₇H₂₁FNO₇[M+H]⁺: 370.130206.

[0377] Found: 370.129173.

EXAMPLE 21

[0378] Compound 21-A: 4-Cyanobenzaldehyde O-methyloxime

[0379] Reaction of 4-cyanobenzaldehyde with methoxylamine hydrochlorideas described in the preparation of compound 3-A gave the title oximeether as a white solid (96% yield). ¹HNMR indicated a 95:5 mixture of E-and Z-isomers. ¹HNMR 400 MHz (CDCl₃) δ (ppm): (E-isomer) 4.02 (3H, s,OCH₃), 7.07 (4H, m, aromatics), 8.06 (1H, s, CH).

[0380] Compound 21-B: N-4-Cyanobenzyl-O-methyl-hydroxylamine

[0381] Reduction of 4-cyanobenzaldehyde O-methyloxime with sodiumcyanoborohydride as described in the preparation of compound 3-B gavethe title hydroxylamine as a clear oil (75% yield). ¹HNMR 400 MHz(CDCl₃) δ (ppm): 3.48 (3H, s, OCH₃), 4.09 (2H, s, NCH₂), 7.48 (2H, m,aromatics), 7.63 (2H, m, aromatics). The hydrochloride salt was obtainedas a white solid: mp 168° C. (dec.). Anal. calcd. for C₉H₁₀N₂O—HCl: C,54.41; H, 5.58; N, 14.10. Found: C, 54.44; H, 5.62; N, 13.94.

[0382] Compound 21-C:N-(4-Cyano-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide

[0383] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with N-(4-cyanobenzyl)-O-methyl-hydroxylamine as described inthe preparation of compound 1-A gave the title amide as white crystals(99% yield): mp 148-149° C. (ethyl acetate-hexane). ¹HNMR 400 MHz(CDCl₃) δ (ppm): 1.75 (6H, s, CH₃), 3.72 (3H, s, OCH₃), 4.86 (2H, s,NCH₂), 6.39 (1H, s, CH), 7.46 (2H, m, aromatics), 7.63 (2H, m,aromatics). Anal. calcd. for C₁₆H₁₆N₂O₅: C, 60.75; H, 5.10; N, 8.86.Found: C, 60.60; H, 4.91; N, 8.78.

[0384] Compound 21:3-[(4-Cyano-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid

[0385] Saponification ofN-(4-cyano-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamideas described in the preparation of compound 1 gave the title material aswhite crystals (92% yield): mp 135-137° C. (dec.)(ethyl acetate-hexane).¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.75 (3H, s, OCH₃), 4.89 (2H, s, NCH₂),6.58 (1H, s, CH), 7.43 (2H, m, aromatics), 7.66 (2H, m, aromatics).Anal. calcd. for C₁₃H₁₂N₂O₅: C, 56.52; H, 4.38; N, 10.14. Found: C,56.70; H, 4.38; N, 10.07.

EXAMPLE 22

[0386] Compound 22-A:[[2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-acetyl]-(4-fluorobenzyl)-aminooxy]-aceticacid.

[0387] A solution[[2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-acetyl]-(4-fluorobenzyl)-aminooxy]-aceticacid tert-butyl ester (0.60 g, 1.46 mmol) in dichloromethane (15 ml) wastreated at 22° C. with trifluoroacetic acid (4 ml) and the resultingmixture was stirred for 2h. Evaporation of the solvent in vacuo gave0.517 g (100% yield) of the title material as a white solid. ¹HNMR 400MHz (CDCl₃) δ (ppm): 1.79 (6H, s, CH₃), 4.41 (2H, s, CH₂), 4.88 (2H, s,CH₂), 6.4 (1H, broad, CH), 7.09 (2H, m, aromatics), 7.35 (2H, m,aromatics). HRMS (ES⁺) calculated for C₁₆H₁₇FNO₇[M+H]⁺: 354.098905.Found: 354.098878.

[0388] Compound 22-B:N-Dimethylcarbamoylmethoxy-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-acetamide

[0389] A solution[[2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-acetyl]-(4-fluorobenzyl)-aminooxy]-aceticacid (0.681 g, 1.93 mmol) in dichloromethane (20 ml) was treated at 22°C. with oxalyl chloride (0.34 ml, 3.9 mmol) and a trace ofN,N-dimethylformamide and the resulting mixture was stirred for 1 h. Thesolvent and excess reagent were then evaporated in vacuo. The residualmaterial was dissolved in dry dichloromethane (10 ml) and added dropwiseto a cold (0° C.) solution of dimethylamine (0.18 g, 4.0 mmol) andpyridine (0.25 ml, 3.2 mmol ) in dichloromethane. After 2 h, thereaction mixture was diluted with ethyl acetate, washed with saturatedsodium bicarbonate and brine and dried over anhydrous magnesiumsulphate. Evaporation of the solvent in vacuo and crystallisation of theresidue from a mixture of ethyl acetate and hexane gave 0.370 g (50%yield) of the title material as a white solid.

[0390]¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.77 (6H, s, CH₃), 2.91 (3H, s,CH₃), 2.97 (3H, s, CH₃), 4.53 (2H, s, CH₂), 4.93 (2H, s, CH₂), 6.43 (1H,s, CH), 7.03 (2H, m, aromatics), 7.41 (2H, m, aromatics). HRMS (ES⁺)calculated for C₁₈H₂₂FN₂O₆[M+H]⁺: 381.146190. Found: 381.146382.

[0391] Compound 22:3-[Dimethylcarbamoylmethoxy-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylicacid

[0392] A solution ofN-dimethylcarbamoylmethoxy-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-(4-fluorobenzyl)-acetamide(0.065 g, 0.17 mmol in tetrahydrofuran (3 ml) was treated at 0° C. with0.34 ml (0.34 mmol) of 1 M aqueous lithium hydroxide. After 1 h, thereaction mixture was acidified with 1N hydrochloric acid and extractedwith ethyl acetate. The organic phase was washed with brine, dried(magnesium sulphate) and evaporated in vacuo. Crystallisation of theresidual solid from a mixture of ethyl acetate and hexane gave 0.043 g(74% yield) of the title material as a white solid: mp 118-120° C. ¹HNMR400 MHz (DMSO-d₆) δ (ppm); (mixture of enol and keto forms, 7:3); enolform: 2.83 (3H, s, NCH₃), 2.88 (3H, s, NCH₃), 4.79 (2H, s, CH₂), 4.94(2H, s, CH₂), 6.47 (1H, s, CH), 7.18 (2H, m, aromatics), 7.38 (2H, m,aromatics), 13.2 (1H, broad, OH), 13.7 (1H, broad, OH). HRMS (ES⁺)calculated for C₁₅H₁₈FN₂O₆[M+H]+: 341.114890. Found: 341.115095.

EXAMPLE 23

[0393] Compound 23-A: 4-Acetamidobenzaldehyde O-methyloxime

[0394] Reaction of 4-acetamidobenzaldehyde with methoxylaminehydrochloride as described in the preparation of compound 3-A gave thetitle oxime ether as a white solid (98% yield). ¹HNMR indicated a 95:5mixture of E- to Z-isomers. ¹HNMR 400 MHz (CDCl₃) δ (ppm): (E-isomer)2.19 (3H, s, CH₃), 3.96 (3H, s, OCH₃), 7.22 (1H, broad s, NH), 7.53 (4H,m, aromatics), 8.01 (1H, s, CH).

[0395] Compound 23-B: N-4-Acetamidobenzyl-O-methyl-hydroxylamine

[0396] Reduction of 4-acetamidobenzaldehyde O-methyloxime with sodiumcyanoborohydride as described in the preparation of compound 3-B gavethe title hydroxylamine as a waxy solid (100% yield). ¹HNMR 400 MHz(CDCl₃) δ (ppm): 2.16 (3H, s, CH₃), 3.49 (3H, s, OCH₃), 4.00 (2H, s,NCH₂), 7.26 (1H, broad s, NH), 7.29 (2H, m, aromatics), 7.46 (2H, m,aromatics). The hydrochloride salt was obtained as a white solid: mp186-188° C. (dec.). Anal. calcd. for C₁₀H₁₄N₂O₂—HCl—H₂O: C, 50.87; H,6.66; N, 11.87. Found: C, 50.77; H, 6.44; N, 12.16.

[0397] Compound 23-C:N-(4-Acetylamino-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide

[0398] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with N-(4-acetamidobenzyl)-O-methyl-hydroxylamine as describedin the preparation of compound 1-A gave the title amide as whitecrystals (92% yield): mp 212-215° C. (dec.) (dichloromethane-hexane).¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.73 (6H, s, CH₃), 2.16 (3H, s, CH₃),3.67 (3H, s, OCH₃), 4.78 (2H, s, NCH₂), 6.39 (1H, s, CH), 7.32 (3H, m,aromatics and NH), 7.45 (2H, m, aromatics). Anal. calcd. for C₁₇H₂₀N₂O₆:C, 57.87; H, 5.86; N, 7.94. Found: C, 57.76; H, 5.68; N, 8.51.

[0399] Compound 23:3-[(4-Acetylamino-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid

[0400] Saponification ofN-(4-acetylamino-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamideas described in the preparation of compound 1 gave the title material aswhite crystals (83% yield): mp 155° C. (dec.)(ethyl acetate). ¹HNMR 400MHz (DMSO-d₆) δ (ppm): mixture of rotamers and keto-enol isomers; 2.02(3H, s, CH₃), 3.71 (3H, s, OCH₃), 4.8 (2H, s, NCH₂), 6.30 (1H, s, CH),7.2 (2H, m, aromatics), 7.52 (2H, m, aromatics), 9.93 (OH). Anal. calcd.for C14H₁₆N₂O₆: C, 54.54; H, 5.23; N, 9.09. Found: C, 54.06; H, 5.57; N,8.39.

EXAMPLE 24

[0401] Compound 24:3-[Carboxymethoxy-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic acid

[0402] A solution of[[2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-acetyl]-(4-fluorobenzyl)-aminooxy]-aceticacid (0.20 g, 0.56 mmol) in tetrahydrofuran (5 ml) was treated at 0° C.with 1.7 ml (1.7 mmol) of 1 M aqueous lithium hydroxide. After 2 h, thereaction mixture was acidified with 1N hydrochloric acid and extractedwith ethyl acetate. The organic layer was washed with brine, dried(magnesium sulphate) and evaporated in vacuo. Crystallisation of theresidual solid from a mixture of ethyl acetate and hexane gave 0.083 g(47% yield) of the title material as a white solid: mp 135-138° C. ¹HNMR400 MHz (DMSO-d₆) δ (ppm): (mixture of enol and keto forms, 7:3); enolform: 4.65 (2H, s, CH₂), 4.92 (2H, s, CH₂), 6.51 (1H, s, CH), 7.18 (2H,m, aromatics), 7.37 (2H, m, aromatics), 13.17 (1H, broad, OH). Anal.calcd for C₁₃H₁₂FNO₇: C, 49.85; H, 3.86; N, 4.47. Found: C, 49.83; H,3.90; N, 4.37.

EXAMPLE 25

[0403] Compound 25-A: 4-Methyl-benzaldehyde O-methyl-oxime

[0404] Reaction of 4-methylbenzaldehyde with methoxylamine hydrochlorideas described in the preparation of compound 3-A gave the title oxime asa clear oil (95% yield), bp 80-85° C./4 torr (bulb to bulb distillation,air bath temperature). HPLC indicated a 94:6 mixture of E- andZ-isomers. ¹HNMR 400 MHz (CDCl₃) δ (ppm): (E-isomer) 2.39 (3H, s, CH₃),3.99 (3H, s, OCH₃), 7.2 (2H, d, J=8.1 Hz, aromatics), 7.5 (2H, d, J=8.1Hz, aromatics), 8.07 (1H, s, CH).

[0405] Compound 25-B: O-Methyl-N-(4-methyl-benzyl)-hydroxylamine

[0406] Reduction of 4-methylbenzaldehyde O-methyloxime with sodiumcyanoborohydride as described in the preparation of compound 3-B gavethe title hydroxylamine as a clear oil (76% yield): bp 70-80° C./3.5torr (bulb to bulb distillation, air bath temperature). ¹HNMR 400 MHz(CDCl₃) δ (ppm): 2.36 (3H, s, CH₃), 3.54 (3H, s, OCH₃), 4.04 (2H, s,NCH₂), 5.7 (broad, NH), 7.17 (2H, d, J=8.1 Hz, aromatics), 7.26 (2H, d,J=8.1 Hz, aromatics). The hydrochloride salt was obtained as a whitesolid: mp 162-164° C. Anal. calcd for C₉H₁₃NO—HCl: C, 57.60; H, 7.51; N,7.46. Found: C, 57.87; H, 7.45; N, 7.25.

[0407] Compound 25-C:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-N-(4-methyl-benzyl)-acetamide

[0408] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with N-(4-methylbenzyl)-O-methyl-hydroxylamine as described inthe preparation of compound 1-A gave the title amide as white crystals(78% yield): mp 108-110° C. (ethyl acetate-hexane). ¹HNMR 400 MHz(CDCl₃) δ (ppm): 1.92 (6H, s, CH₃), 2.5 (3H, s, CH₃), 3.84 (3H, s,OCH₃), 4.97 (2H, s, NCH₂), 6.57 (1H, s, CH), 7.31 (2H, d, J=8.1 Hz,aromatics), 7.42 (2H, d, J=8.1 Hz, aromatics). Anal. calcd forC₁₆H₁₉NO₅: C, 62.94; H, 6.27; N, 4.59. Found: C, 63.14; H, 5.93; N,4.34.

[0409] Compound 25:2-Hydroxy-3-[methoxy-(4-methyl-benzyl)-carbamoyl]-acrylic acid

[0410] Saponification of2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-N-(4-methyl-benzyl)-acetamideas described in the preparation of compound 1 gave the title material asa white solid (95% yield): mp 108-111° C. (dec) (ethyl acetate-hexane).¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.37 (3H, s, CH₃), 3.72 (3H, s, OCH₃),4.83 (2H, s, NCH₂), 6.59 (1H, s, CH), 7.18 (2H, d, J=8.1 Hz, aromatics),7.25 (2H, d, J=8.1 Hz, aromatics). Anal. calcd for C₁₃H₁₅NO₅: C, 58.86;H, 5.70; N, 5.28. Found: C, 58.66; H, 5.71; N, 5.23.

EXAMPLE 26

[0411] Compound 26-A: 4-Fluoro-3-methyl-benzaldehyde O-methyl-oxime

[0412] Reaction of 4-fluoro-3-methyl-benzaldehyde with methoxylaminehydrochloride as described in the preparation of compound 3-A gave thetitle oxime ether as a clear oil after chromatography on silica gel(elution hexane-ethyl acetate 8:2) (100% yield). ¹HNMR indicated a 9:1mixture of E- and Z-isomers. ¹HNMR 400 MHz (CDCl₃) δ (ppm): (E-isomer)2.29 (3H, broad s, CH₃), 3.96 (3H, s, OCH₃), 7.0 (1H, m, aromatic), 7.34(1H, m, aromatic), 7.4 (1H, m, aromatic), 8.0 (1H, s, CH).

[0413] Compound 26-B:N-(4-Fluoro-3-methyl-benzyl)-O-methyl-hydroxylamine

[0414] Reduction of 4-fluoro-3-methyl-benzaldehyde O-methyloxime withsodium cyanoborohydride as described in the preparation of compound 3-Bgave the title hydroxylamine as a clear oil after chromatography onsilica gel (elution hexane-ethyl acetate 8:2) (94% yield). ¹HNMR 400 MHz(CDCl₃) δ (ppm): 2.27 (3H, broad s, CH₃), 3.50 (3H, s, OCH₃), 3.97 (2H,broad s, NCH₂), 5.67 (1H, broad, NH), 6.95 (1H, m, aromatic), 7.11-7.17(2H, m, aromatics. The hydrochloride salt was obtained as a white solid:

[0415] mp 162° C. Anal. calcd for C₉H₁₂FNO—HCl: C, 52.56; H, 6.37; N,6.81.

[0416] Found: C, 52.80; H, 6.33; N, 6.70.

[0417] Compound 26-C:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-Fluoro-3-methyl-benzyl)-N-methoxy-acetamide

[0418] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with N-(4-fluoro-3-methyl-benzyl)-O-methyl-hydroxylamine asdescribed in the preparation of compound 1-A gave the title amide aswhite crystals (95% yield): mp 107-108° C. (ethyl acetate-hexane). ¹HNMR400 MHz (CDCl₃) δ (ppm): 1.75 (6H, s, CH₃), 2.26 (3H, broad s, CH₃),3.69 (3H, s, OCH₃), 4.75 (2H, s, NCH₂), 6.39 (1H, s, CH), 6.95 (1H, m,aromatic), 7.13-7.19 (2H, m, aromatics). Anal. calcd for C₁₆H₁₈FNO₅: C,59.43; H, 5.61; N, 4.33. Found: C, 59.24; H, 5.47; N 4.29.

[0419] Compound 26:3-[(4-Fluoro-3-methyl-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid

[0420] Saponification of2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-3-methyl-benzyl)-N-methoxy-acetamideas described in the preparation of compound 1 gave the title material aswhite crystals (96% yield): mp 120-122° C. (ethyl acetate-hexane). ¹HNMR400 MHz (CDCl₃) δ (ppm): 2.27 (3H, broad s, CH₃), 3.71 (3H, s, OCH₃),4.77 (2H, s, NCH₂), 6.56 (1H, s, CH), 6.97 (1H, m, aromatic), 7.1-7.15(2H, m, aromatics). Anal. calcd for C₁₃H₁₄FNO₅: C, 55.12; H, 4.98; N,4.94. Found: C, 55.06; H, 4.91; N, 4.83.

EXAMPLE 27

[0421] Compound 27-A: 3-Fluoro-4-methyl-benzaldehyde O-methyl-oxime

[0422] Reaction of 3-fluoro-4-methyl-benzaldehyde with methoxylaminehydrochloride as described in the preparation of compound 3-A gave thetitle oxime ether as a clear oil (94% yield). ¹HNMR indicated a 9:1mixture of E- and Z-isomers. ¹HNMR 400 MHz (CDCl₃) δ (ppm): (E-isomer)2.28 (3H, broad s, CH₃), 3.97 (3H, s, OCH₃), 7.15-7.29 (3H, m,aromatics), 7.99 (1H, s, CH).

[0423] Compound 27-B:N-(3-Fluoro-4-methyl-benzyl)-O-methyl-hydroxylamine

[0424] Reduction of 3-fluoro-4-methyl-benzaldehyde O-methyloxime withsodium cyanoborohydride as described in the preparation of compound 3-Bgave the title hydroxylamine as a clear oil after chromatography onsilica gel (elution hexane-ethyl acetate 8:2) (57% yield). ¹HNMR 400 MHz(CDCl₃) δ (ppm): 2.25 (3H, broad s, CH₃), 3.50 (3H, s, OCH₃), 3.99 (2H,broad s, NCH₂), 5.71 (1H, broad, NH), 7.01 (2H, m, aromatics), 7.13 (1H,m, aromatic). The hydrochloride salt was obtained as a white solid: mp140-142° C. Anal. calcd for C₉H₁₂FNO—HCl: C, 52.56; H, 6.37; N, 6.81.

[0425] Found: C, 52.63; H, 6.30; N, 6.78.

[0426] Compound 27-C:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(3-fluoro-4-methyl-benzyl)-N-methoxy-acetamide

[0427] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with N-(3-fluoro-4-methyl-benzyl)-O-methyl-hydroxylamine asdescribed in the preparation of compound 1-A gave the title amide aswhite crystals (100% yield): mp 131° C. (ethyl acetate-hexane). ¹HNMR400 MHz (CDCl₃) δ (ppm): 1.75 (6H, s, CH₃), 2.25 (3H, broad s, CH₃),3.69 (3H, s, OCH₃), 4.77 (2H, s, NCH₂), 6.39 (1H, s, CH), 7.0-7.03 (2H,m, aromatics), 7.13 (1H, m, aromatic). Anal. calcd for C₁₆H₁₈FNO₅: C,59.43; H, 5.61; N, 4.33. Found: C, 59.51; H, 5.60; N, 4.24.

[0428] Compound 27:3-[(3-Fluoro-4-methyl-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid

[0429] Saponification of2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(3-fluoro-4-methyl-benzyl)-N-methoxy-acetamideas described in the preparation of compound 1 gave the title material aswhite crystals (100% yield): mp 99° C. (ethyl acetate-hexane). ¹HNMR 400MHz (CDCl₃) δ (ppm): 2.26 (3H, broad s, CH₃), 3.72 (3H, s, OCH₃), 4.79(2H, s, NCH₂), 6.56 (1H, s, CH), 7.0 (2H, m, aromatics), 7.16 (1H, m,aromatic). Anal. calcd for C₁₃H₁₄FNO₅: C, 55.12; H, 4.98; N, 4.94.Found: C, 54.82; H, 4.90; N, 4.80.

EXAMPLE 28

[0430] Compound 28-A: 4-Trifluoromethyl-benzaldehyde O-methyloxime

[0431] Reaction of 4-trifluoromethylbenzaldehyde with methoxylaminehydrochloride as described in the preparation of compound 3-A gave thetitle oxime ether as a clear oil (100% yield). ¹HNMR indicated a 9:1mixture of E- and Z-isomers. ¹HNMR 400 MHz (CDCl₃) δ (ppm): (E-isomer)4.00 (3H, s, OCH₃), 7.62 (2H, m, aromatics), 7.69 (2H, m, aromatics),8.08 (1H, s, CH).

[0432] Compound 28-B:O-Methyl-N-(4-trifluoromethyl-benzyl)-hydroxylamine

[0433] Reduction 4-trifluoromethyl-benzaldehyde O-methyloxime of withsodium cyanoborohydride as described in the preparation of compound 3-Bgave the title hydroxylamine as a clear oil (73% yield). ¹HNMR 400 MHz(CDCl₃) δ (ppm): 3.49 (3H, s, OCH₃), 4.09 (2H, s, NCH₂), 5.80 (1H, broads, NH), 7.48 (2H, m, aromatics), 7.60 (2H, m, aromatics). Thehydrochloride salt was obtained as a white solid: mp 132-133° C. Anal.calcd for C₉H₁₀F₃NO—HCl: C, 44.74; H, 4.59; N, 5.80. Found: C, 44.71; H,4.53; N, 5.68.

[0434] Compound 28-C:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-N-(4-trifluoromethyl-benzyl)-acetamide

[0435] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with O-methyl-N-(4-trifluoromethyl-benzyl)-hydroxylamine asdescribed in the preparation of compound 1-A gave the title amide aswhite crystals (97% yield): mp 110° C. (ethyl acetate-hexane). ¹HNMR 400MHz (CDCl₃) δ (ppm): 1.76 (6H, s, CH₃), 3.71 (3H, s, OCH₃), 4.87 (2H, s,NCH₂), 6.40 (1H, s, CH), 7.47 (2H, m, aromatics), 7.59 (2H, m,aromatics).

[0436] Anal. calcd for C₁₆H₁₆F₃NO₅: C, 53.49; H, 4.49; N, 3.90. Found:C, 53.48; H, 4.53; N, 3.83.

[0437] Compound 28:2-Hydroxy-3-[methoxy-(4-trifluoromethyl-benzyl)-carbamoyl]-acrylic acid

[0438] Saponification of2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-N-(4-trifluoromethyl-benzyl)-acetamideas described in the preparation of compound 1 gave the title material aswhite crystals (94% yield): mp 108-110° C. (ethyl acetate-hexane). ¹HNMR400 MHz (CDCl₃) δ (ppm): 3.74 (3H, s, OCH₃), 4.90 (2H, s, NCH₂), 6.58(1H, s, CH), 7.45 (2H, m, aromatics), 7.62 (2H, m, aromatics). Anal.calcd for C₁₃H₁₂F₃NO₅: C, 48.91; H, 3.78; N, 4.38. Found: C, 48.96; H,3.79; N, 4.29.

EXAMPLE 29

[0439] Compound 29-A: 4-Fluoro-2-trifluoromethyl-benzaldehydeO-methyloxime

[0440] Reaction of 4-fluoro-2-trifluoromethyl-benzaldehyde withmethoxylamine hydrochloride as described in the preparation of compound3-A gave the title oxime ether as a clear oil (93% yield).

[0441]¹HNMR indicated a 92:8 mixture of E- and Z-isomers. ¹HNMR 400 MHz(CDCl₃) δ (ppm): (E-isomer) 4.00 (3H, s, OCH₃), 7.25 (1H, m, aromatic),7.37 (1H, m, aromatic), 8.08 (1H, m, aromatic), 8.36 (1H, broad s, CH).

[0442] Compound 29-B:N-(4-Fluoro-2-trifluoromethyl-benzyl)-O-methyl-hydroxylamine

[0443] Reduction of 4-fluoro-2-trifluoromethyl-benzaldehydeO-methyloxime with sodium cyanoborohydride as described in thepreparation of compound 3-B gave the title hydroxylamine as a clear oilafter chromatography on silica gel (elution hexane-ethyl acetate 8:2)(35% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.55 (3H, s, OCH₃), 4.21(2H, s, NCH₂), 5.76 (1H, broad, NH), 7.26 (1H, m, aromatic), 7.38 (1H,m, aromatic), 7.64 (1H, m, aromatic). The hydrochloride salt wasobtained as a white solid: mp 138-140° C. Anal. calcd for C₉H₉F₄NO—HCl:C, 41.64; H, 3.88; N, 5.39. Found: C, 41.49; H, 3.68; N, 5.26.

[0444] Compound 29:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-trifluoromethyl-benzyl)-N-methoxy-acetamide.

[0445] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride withN-(4-fluoro-2-trifluoromethyl-benzyl)-O-methyl-hydroxylamine asdescribed in the preparation of compound 1-A gave the title amide aswhite crystals (98% yield): mp 129-130° C. (ethyl acetate-hexane).

[0446]¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.76 (6H, s, CH₃), 3.69 (3H, s,OCH₃), 5.04 (2H, s, NCH₂), 6.45 (1H, s, CH), 7.21 (1H, m, aromatic),7.37 (1H, m, aromatic), 7.47 (1H, m, aromatic). Anal. calcd forC₁₆H₁₅F₄NO₅: C, 50.94; H, 4.01; N, 3.71. Found: C ,50.96; H, 4.07; N,3.66.

EXAMPLE 30

[0447] Compound 30-A: 2-Chloro-4-fluoro-benzaldehyde O-methyloxime

[0448] Reaction of 2-chloro-4-fluoro-benzaldehyde with methoxylaminehydrochloride as described in the preparation of compound 3-A gave thetitle oxime ether as a clear oil (93% yield). ¹HNMR indicated a 9:1mixture of E- and Z-isomers. ¹HNMR 400 MHz (CDCl₃) δ (ppm): (E-isomer)3.99 (3H, s, OCH₃), 6.99 (1H, m, aromatic), 7.12 (1H, m, aromatic), 7.87(1H, m, aromatic), 8.41 (1H, s, CH).

[0449] Compound 30-B:N-(2-Chloro-4-fluoro-benzyl)-O-methyl-hydroxylamine

[0450] Reduction of 2-chloro-4-fluoro-benzaldehyde O-methyloxime withsodium cyanoborohydride as described in the preparation of compound 3-Bgave the title hydroxylamine as a clear oil after chromatography onsilica gel (elution dichloromethane-ethyl acetate 95:5) (54% yield).

[0451]¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.55 (3H, s, OCH₃), 4.16 (2H, s,NCH₂), 6.99 (1H, m, aromatic), 7.15 (1H, dd, J=2.5 Hz and J=8.6 Hz,aromatic), 7.41 (1H, dd, J=6.0 Hz and J=8.6 Hz, aromatic). Thehydrochloride salt was obtained as a white solid: mp 159° C. Anal. calcdfor C₈H₉ClFNO—HCl: C, 42.50; H, 4.46; N, 6.20. Found: C, 42.50; H, 4.36;N, 5.98.

[0452] Compound 30-C:N-(2-Chloro-4-fluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide

[0453] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with N-(2-chloro-4-fluoro-benzyl)-O-methyl-hydroxylamine asdescribed in the preparation of compound 1-A gave the title amide aswhite crystals (97% yield): mp 127-128° C. (ethyl acetate-hexane). ¹HNMR400 MHz (CDCl₃) δ (ppm): 1.76 (6H, s, CH₃), 3.70 (3H, s, OCH₃), 4.95(2H, s, NCH₂), 6.41 (1H, s, CH), 6.96 (1H, m, aromatic), 7.13 (1H, dd,J=2.5 Hz and J=8.7 Hz, aromatic), 7.38 (1H, dd, J=6.1 Hz and J=8.6 Hz,aromatic). Anal. calcd for C₁₅H₁₅ClFNO₅: C, 52.41; H, 4.39; N, 4.07.Found: C, 52.49; H, 4.15; N, 3.76.

[0454] Compound 30:3-[(2-Chloro-4-fluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid

[0455] Saponification ofN-(2-chloro-4-fluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamideas described in the preparation of compound 1 gave the title material aswhite crystals (98% yield): mp 140-143° C. (ethyl acetate-hexane). ¹HNMR400 MHz (DMSO-d₆) δ (ppm): mixture of keto-enol forms 25:75; enol: 3.72(3H, s, OCH₃), 4.96 (2H, s, NCH₂), 6.33 (1H, s, CH),. 7.25 (1H, m,aromatic), 7.41 (1H, m, aromatic), 7.50 (1H, m, aromatic); keto: 3.64(3H, s OCH₃), 3.98 (2H, s, CH₂), 4.84 (2H, s, CH₂). Anal. calcd forC₁₂H₁₁ClFNO₅: C, 47.46; H, 3.65; N, 4.61. Found: C, 47.45; H, 3.61; N,4.56.

EXAMPLE 31

[0456] Compound 31-A: 2-Isopropoxy-benzaldehyde O-methyloxime

[0457] Reaction of 2-isopropoxybenzaldehyde (Hach, Collect. Czech.Commun., 23, 1958, 1902-1907) with methoxylamine hydrochloride asdescribed in the preparation of compound 3-A gave the title oxime etheras a clear oil after chromatography on silica gel (elution hexane-ethylacetate 8:2) (96% yield). ¹HNMR indicated a 95:5 mixture of E- andZ-isomers. ¹HNMR 400 MHz (CDCl₃) δ (ppm): (E-isomer) 1.33 (6H, d, J=6.1Hz, CH₃), 3.97 (3H, s, OCH₃), 4.56 (1H, m, CH), 6.90 (2H, m, aromatics),7.30 (1H, m, aromatic), 7.79 (1H, dd, J=2.0 Hz and J=7.6 Hz, aromatic),8.47 (1H, s, CH).

[0458] Compound 31-B: N-(2-Isopropoxy-benzyl)-O-methyl-hydroxylamine

[0459] Reduction of 2-isopropoxy-benzaldehyde O-methyloxime with sodiumcyanoborohydride as described in the preparation of compound 3-B gavethe title hydroxylamine as a clear oil after chromatography on silicagel (elution hexane-ethyl acetate 8:2) (83% yield). ¹HNMR 400 MHz(CDCl₃) δ (ppm): 1.35 (6H, d, J=6.1 Hz, CH₃), 3.56 (3H, s, OCH₃), 4.07(2H, broad s, NCH₂), 4.59 (1H, m, CH), 6.08 (1H, broad s, NH), 6.86-6.91(2H, m, aromatics), 7.20-7.24 (2H, m, aromatics). The hydrochloride saltwas obtained as a white solid: mp 90° C. Anal. calcd for C₁₁H₁₇NO₂—HCl:C, 57.02; H, 7.83; N, 6.04. Found: C, 56.93; H, 7.64; N, 5.96

[0460] Compound 31-C:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(2-isopropoxy-benzyl)-N-methoxy-acetamide

[0461] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with N-(2-isopropoxy-benzyl)-O-methyl-hydroxylamine asdescribed in the preparation of compound 1-A gave the title amide aswhite crystals (93% yield): mp 103° C. (ethyl acetate-hexane). ¹HNMR 400MHz (CDCl₃) δ (ppm): 1.34 (6H, d, J=6.0 Hz, CH₃), 1.75 (6H, s, CH₃),3.68 (3H, s, OCH₃), 4.60 (1H, m, CH), 4.95 (2H, broad s, NCH₂), 6.44(1H, s, CH), 6.89 (2H, m, aromatics), 7.2-7.3 (2H, m, aromatics). Anal.calcd for C₁₈H₂₃NO₆: C, 61.88; H, 6.64; N, 4.01. Found: C, 61.22; H,6.33; N, 3.87.

[0462] Compound 31:2-Hydroxy-3-[(2-isopropoxy-benzyl)-methoxy-carbamoyl]-acrylic acid

[0463] Saponification of2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(2-isopropoxy-benzyl)-N-methoxy-acetamideas described in the preparation of compound 1 gave the title material asa white syrup (92% yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.33 (6H, d,J=6.1 Hz, CH₃) 3.69 (3H, s, OCH₃), 4.60 (1H, m, CH), 4.91 (2H, s, NCH₂),6.60 (1H, s, CH), 6.87-6.92 (2H, m, aromatics), 7.21-7.28 (2H, m,aromatics). HRMS (MAB N₂) calculated for C₁₅H₁₉NO₆ [M⁺]: 309.121238:found: 309.120947.

EXAMPLE 32

[0464] Compound 32-A: 4-Formyl-benzoic acid tert-butyl ester

[0465] A suspension of 4-carboxybenzaldehyde (5.2 g, 34.6 mmol) intetrahydrofuran (130 ml) was treated under argon with di-tert-butyldicarbonate (15.3 g, 70.0 mmol) and 4-dimethylaminopyridine (1.28 g,10.0 mmol) and the resulting mixture was stirred at 22° C. for 72 h.After dilution with dichloromethane, the reaction mixture was washedsuccessively with 5% citric acid, saturated sodium bicarbonate and brineand dried over anhydrous magnesium sulphate. Evaporation of the solventunder reduced pressure and chromatography of the residue on silica gel(elution toluene-ethyl acetate, 95:5) yielded 2.43 g (34% yield) of thetitle ester as a white solid. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.61 (9H,s, t-Bu), 7.92 (2H, d, J=8.3 Hz, aromatics), 8.13 (2H, d, J=8.3 Hz,aromatics), 10.09 (1H, s, CH).

[0466] Compound 32-B: 4-(Methoxyimino-methyl)-benzoic acid tert-butylester

[0467] Reaction of 4-formyl-benzoic acid tert-butyl ester withmethoxylamine hydrochloride as described in the preparation of compound3-A gave the title oxime ether as a clear oil after chromatography onsilica gel ( elution hexane-ethyl acetate, 96:4) (79% yield). ¹HNMR 400MHz (CDCl₃) δ (ppm): 1.60 (9H, s, t-Bu), 4.00 (3H, s, OCH₃), 7.62 (2H,d, J=8.0 Hz, aromatics), 7.97 (2H, d, J=8.0 Hz, aromatics), 8.08 (1H, s,CH).

[0468] Compound 32-C: 4-(Methoxyamino-methyl)-benzoic acid tert-butylester

[0469] Reduction of 4-(methoxyimino-methyl)-benzoic acid tert-butylester with sodium cyanoborohydride as described in the preparation ofcompound 3-B gave the title hydroxylamine as a clear oil afterchromatography on silica gel (elution hexane-ethyl acetate 8:2) (56%yield). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.59 (9H, s, t-Bu), 3.49 (3H, s,OCH₃), 4.09 (2H, s, NCH₂), 7.41 (2H, d, J=8.6 Hz, aromatics), 7.96 (2H,d, J=8.6 Hz, aromatics). The hydrochloride salt was obtained as a whitesolid: mp 130-132° C. Anal. calcd for C₁₃H₁₉NO₃—HCl: C, 57.04; H, 7.36;N, 5.12. Found: C, 56.90; H, 7.27; N, 5.00.

[0470] Compound 32-D:4-({[2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl]-methoxy-amino}-methyl)-benzoicacid tert-butyl ester

[0471] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with 4-(methoxyamino-methyl)-benzoic acid tert-butyl ester asdescribed in the preparation of compound 1-A gave the title amide aswhite crystals (93% yield): mp 137-138° C. (dichloromethane-hexane).

[0472]¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.58 (9H, s, t-Bu), 1.76 (6H, s,CH₃), 3.67 (3H, s, OCH₃), 4.87 (2H, s, NCH₂), 6.40 (1H, s, CH), 7.39(2H, d, J=8.2 Hz, aromatics), 7.95 (2H, d, J=8.2 Hz, aromatics). Anal.calcd for C₂₀H₂₅NO₇: C, 61.37; H. 6.44; N, 3.58. Found: C, 61.23; H,6.25; N, 3.52.

[0473] Compound 32-E:4-({[2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl]-methoxy-amino}-methyl)-benzoicacid

[0474] A solution of4-({[2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl]-methoxy-amino}-methyl)-benzoicacid tert-butyl ester (0.60 g, 1.53 mmol) in dichloromethane (25 ml) wastreated at 22° C. with trifluoroacetic acid (6 ml) and the resultingmixture was stirred for 1 h. Evaporation of the solvent in vacuo andrecrystallization of the solid residue gave 0.457 g (89% yield) of thetitle material as white crystals: mp 217-219° C.(dichloromethane-hexane). ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 1.70 (6H, s,CH₃), 3.72 (2H, s, OCH₃), 4.89 (2H, s, NCH₂), 6.18 (1H, s, CH), 7.39(2H, d, J=8.3 Hz, aromatics), 7.91 (2H, d, J=8.3 Hz, aromatics), 12.9(1H, broad s, OH). Anal. calcd for C₁₆H₁₇NO₇: C, 57.31; H, 5.11; N,4.18. Found: C, 57.33; H, 5.08; N, 4.25.

[0475] Compound 32:4-{[(3-Carboxy-3-hydroxy-acryloyl)-methoxy-amino]-methyl}-benzoic acidmethyl ester

[0476] Saponification of4-({[2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl]-methoxy-amino}-methyl)-benzoicacid as described in the preparation of compound 1 gave the titlematerial as a white solid (66% yield); mp 123-125° C. ¹HNMR 400 MHz(DMSO-d₆) δ (ppm):mixture of enol and keto forms, 7:3; enol form, 3.75(3H, s, OCH₃), 4.97 (2H, s, NCH₂), 6.34 (1H, s, CH), 7.4 (2H, d, J=8.3Hz, aromatics), 7.92 (2H, d, J=8.3 Hz, aromatics), 13.2 (2H, broad, OH);keto form, 3.65 (3H, s, OCH₃), 3.97 (2H, s, CH₂), 4.87 (2H, s, NCH₂).Anal. calcd for C₁₃H₁₃NO7-0.2 H₂O: C, 52.25; H, 4.52; N, 4.69. Found: C,52.17; H, 4.42; N, 4.64.

EXAMPLE 33

[0477] Compound 33:4-({[2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl]-methoxy-amino}-methyl)-N-methyl-benzamide.

[0478] A solution of4-({[2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl]-methoxy-amino}-methyl)-benzoicacid (0.150 g, 0.45 mmol) in dichloromethane (2 ml) was treated at 22°C. with oxalyl chloride (0.08 ml) and a trace (capillary) ofN,N-dimethylformamide and the resulting mixture was stirred for 2 h. Thesolvent and excess reagent were evaporated in vacuo and the residue wasdissolved in dichloromethane (2 ml). This solution was added dropwise toa cold (5° C.) solution of methylamine (0.5 mmol, 0.25 ml of a 2Msolution in tetrahydrofuran) and pyridine (0.01 ml) in dichloromethane(2 ml). After 1 h at 22° C., the reaction mixture was diluted with ethylacetate, washed successively with 0.1 N hydrochloric acid, saturatedsodium bicarbonate, brine and dried over anhydrous magnesium sulphate.Evaporation of the solvent under reduced pressure and chromatography ofthe residue on silica gel (elution ethyl acetate and acetonitrile, 0 to5%) yielded 0.060 g (38% yield) of the title amide as a white solid.¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 1.69 (6H, s, CH₃), 2.77 (3H, d, J=4.5Hz, NCH₃), 3.72 (2H, s, OCH₃), 4.85 (2H, s, NCH₂), 6.18 (1H, s, CH),7.35 (2H, d, J=8.2 Hz, aromatics), 7.79 (2H, d, J=8.2 Hz, aromatics),8.41 (1H, broad q, NH).

EXAMPLE 34

[0479] Compound 34-A: 3-(4-Fluorophenyl)-propionaldehyde O-methyloxime

[0480] Reaction of 3-(4-fluorophenyl)-propionaldehyde (Dickinson, R. P.;Dack, K. N.; Steele, J.; Tute, M. S. Bioorg. Med. Chem. Lett., 6, 14,1996, 1691-1696) with methoxylamine hydrochloride as described in thepreparation of compound 3-A gave the title oxime ether as a clear oil(97% yield), bp 65-75° C./1.5 torr (bulb to bulb distillation, air bathtemperature). ¹HNMR indicated a 6:4 mixture of E- and Z-isomers.

[0481]¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.51 and 2.65 (2H, 2 m, CH₂), 2.8(2H, m, CH₂), 3.84 and 3.88 (3H, 2 s, OCH₃), 6.67 (t, J=5.5 Hz, CH), 7.0(2H, m, aromatics), 7.16 (2H, m, aromatics), 7.40 (t, J=4.2 Hz, CH).

[0482] Compound 34-B:N-[3-(4-Fluorophenyl)-propyl]-O-methyl-hydroxylamine

[0483] Reduction of 3-(4-fluorophenyl)-propionaldehyde O-methyloximewith sodium cyanoborohydride as described in the preparation of compound3-B gave the title hydroxylamine as a clear oil after chromatography onsilica gel and distillation in vacuo (75% yield): bp 70-75° C./0.7 torr(bulb to bulb distillation, air bath temperature). ¹HNMR 400 MHz (CHCl₃)δ (ppm): 1.85 (2H, m, CH₂), 2.68 (2H, t, J=7.9 Hz, CH₂), 2.95 (2H, t,J=7.1 Hz, CH₂), 3.56 (3H, s, OCH₃), 5.58 (1H, broad, NH), 6.99 (2H, m,aromatics), 7.17 (2H, m, aromatics). The hydrochloride salt was obtainedas a white solid: mp 97-100° C. Anal. calcd for C₁₀H₁₄FNO—HCl: C, 54.67;H, 6.88; N, 6.38. Found: C, 54.72; H, 6.71; N, 6.42.

[0484] Compound 34-C:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-[3-(4-fluoro-phenyl)-propyl]-N-methoxy-acetamide

[0485] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with N-[3-(4-fluorophenyl)-propyl]-O-methyl-hydroxylamine asdescribed in the preparation of compound 1-A gave the title amide aswhite crystals (97% yield): mp 90-91° C. (ethyl acetate-hexane). ¹HNMR400 MHz (CDCl₃) δ (ppm): 1.77 (6H, s, CH₃), 1.98 (2H, m, CH₂), 2.64 (2HJ=7.9 Hz, CH₂), 3.71 (2H, t, J=7.6 Hz, NCH₂), 3.73 (3H, s, OCH₃), 6.41(1H, broad s, CH), 6.98 (2H, m, aromatics), 7.16 (2H, m, aromatics).Anal. calcd for C₁₇H₂₀FNO₅: C, 60.53; H, 5.98; N, 4.15. Found: C, 60.43;H, 5.99; N, 4.09.

[0486] Compound 34:3-{[3-(4-Fluorophenyl)-propyl]-methoxy-carbamoyl}-2-hydroxy-acrylic acid

[0487] Saponification of2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-[3-(4-fluoro-phenyl)-propyl]-N-methoxy-acetamideas described in the preparation of compound 1 gave the title material aswhite crystals (98% yield): mp 86° C. (dec) (ether-hexane). ¹HNMR 400MHz (CDCl₃) δ (ppm): 2.0 (2H, m, CH₂), 2.65 (2H, t, J=7.8 Hz, CH₂), 3.72(2H, t, J=7.1 Hz, NCH₂), 3.75 (3H, s, OCH₃), 6.57 (1H, s, CH), 7.0 (2H,m, aromatics), 7.17 (2H, m, aromatics). Anal. calcd for C₁₄H₁₆FNO₅: C,56.56; H. 5.43; N, 4.71.

[0488] Found: C, 56.78; H, 5.49; N, 4.69.

EXAMPLE 35

[0489] Compound 35-A: 3-(3,4-Dichlorophenyl)-propionaldehydeO-methyloxime

[0490] Reaction of 3-(3,4-dichlorophenyl)-propionaldehyde (Heck, J.Amer. Chem. Soc., 90, 1968, 5526) with methoxylamine hydrochloride asdescribed in the preparation of compound 3-A gave the title oxime etheras a clear oil (91% yield), bp 80-90° C./0.5 torr (bulb to bulbdistillation, air bath temperature). ¹HNMR indicated a 55:45 mixture ofE- and Z-isomers.

[0491]¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.63 and 2.76 (2H, 2 m, CH₂), 2.9(2H, m, CH₂), 3.96 and 4.01 (3H, 2 s, OCH₃), 6.77 (t, J=5.5 Hz, CH),7.16-7.5 (3H, m, aromatics and CH).

[0492] Compound 35-B:N-[3-(3,4-Dichlorophenyl)-propyl]-O-methyl-hydroxylamine

[0493] Reduction of 3-(3,4-dichlorophenyl)-propionaldehyde O-methyloximewith sodium cyanoborohydride as described in the preparation of compound3-B gave the title hydroxylamine as a clear oil after chromatography onsilica gel and distillation in vacuo (48% yield): bp 75-80° C./0.3 torr(bulb to bulb distillation, air bath temperature). ¹HNMR 400 MHz (CHCl₃)δ (ppm): 1.81 (2H, m, CH₂), 2.63 (2H, t, J=7.8 Hz, CH₂), 2.90 (2H, t,J=7.1 Hz, CH₂), 3.52 (3H, s, OCH₃), 5.55 (broad, NH), 7.01 (1H, dd,J=2.0 Hz and J=8.1 Hz, aromatic), 7.27 (1H, broad d, aromatic), 7.32(1H, d, J=8.1 Hz, aromatic). The hydrochloride salt was obtained as awhite solid: mp 81-83° C. Anal. calcd for C₁₀H₁₃Cl₂NO—HCl: C, 44.39; H,5.22; N, 5.18. Found: C, 44.57; H, 5.05; N, 5.18.

[0494] Compound 35-C:N-[3-(3,4-Dichloro-phenyl)-propyl]-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide

[0495] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with N-[3-(3,4-dichlorophenyl)-propyl]-O-methyl-hydroxylamineas described in the preparation of compound 1-A gave the title amide aswhite crystals (95% yield): mp 105-106° C. (ethyl acetate-hexane). ¹HNMR400 MHz (CDCl₃) δ (ppm): 1.91 (6H, s, CH₃), 2.13 (2H, m, CH₂), 2.77 (2H,t, J=7.9 Hz, CH₂), 3.86 (2H, t, J=7.0 Hz, NCH₂), 3.88 (3H, s, OCH₃),6.54 (1H, broad s, CH), 7.2 (H, broad dd, aromatic), 7.44 (1H, broad d,J=2 Hz, aromatic), 7.50 (1H, d, J=8.1 Hz, aromatic). Anal. calcd forC₁₇H₁₉Cl₂NO₅: C, 52.59; H, 4.93; N, 3.61. Found: C, 52.68; H, 5.08; N,3.50.

[0496] Compound 35:3-{[3-(3,4-Dichlorophenyl)-propyl]-methoxy-carbamoyl}-2-hydroxy-acrylicacid

[0497] Saponification ofN-[3-(3,4-dichloro-phenyl)-propyl]-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamideas described in the preparation of compound 1 gave the title material aswhite crystals (97% yield): mp 106° C. (dec) (ethyl acetate-hexane).

[0498]¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.97 (2H, m, CH₂), 2.61 (2H, t,J=7.7 Hz, CH₂), 3.71 (2H, t, J=6.9 Hz, NCH₂), 3.73 (3H, s, OCH₃), 6.54(1H, s, CH), 7.03 (1H, dd, J=2.0 Hz and J=8.24 Hz, aromatic), 7.28 (1H,d, J=2.0 Hz, aromatic) 7.35 (1H, d, J=8.24 Hz, aromatic). Anal. calcdfor C₁₄H₁₅Cl₂NO₅: C, 48.29; H, 4.34; N, 4.02. Found: C, 48.34; H, 4.24;N, 3.98.

EXAMPLE 36

[0499] Compound 36-A: (3,4-Dichlorobenzylideneaminooxy)-acetic acidtert-butyl ester

[0500] Condensation of 3,4-dichlorobenzaldehyde with hydroxylaminehydrochloride followed by reaction with tert-butyl bromoacetate using aprocedure similar to the one described for the preparation of compound6-A gave the title oxime ether as a clear oil after chromatography onsilica gel (elution dichloromethane-hexane 1:1) (94% yield). ¹HNMR 400MHz (CDCl₃) δ (ppm): 1.52 (9H, s, t-Bu), 4.63 (2H, s, OCH₂), 7.41 (1H,dd, J=1.9 Hz and J=8.6 Hz, aromatic), 7.47 (1H, d, J=8.6 Hz, aromatic),7.71 (1H, d, J=1.9 Hz, aromatic), 8.13 (1H, s, CH).

[0501] Compound 36-B: [N-(3,4-Dichlorobenzyl)aminooxy]-acetic acidtert-butyl ester

[0502] Reduction of (3,4-dichlorobenzylideneaminooxy)-acetic acidtert-butyl ester as described in the preparation of compound 3-B gavethe title hydroxylamine as a clear oil (50% yield). ¹HNMR 400 MHz (C₆D₆)δ (ppm): 1.4 (9H, s, t-Bu), 3.6 (2H, broad s, NCH₂), 4.1 (2H, s, OCH₂),6.35 (1H, broad, NH), 6.75 (1H, dd, J=2.0 Hz and J=8.1 Hz, aromatic),7.07 (1H, d, J=8.1 Hz, aromatic), 7.24 (H, d, J=2.0 Hz, aromatic).

[0503] Compound 36:{(3,4-Dichlorobenzyl)-[2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-acetyl]-aminooxy}-aceticacid tert-butyl ester

[0504] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with [N-(3,4-dichlorobenzyl)aminooxy]-acetic acid tert-butylester as described in the preparation of compound 1-A gave the titleamide as white crystals (49% yield): mp 127-129° C. (ethylacetate-hexane).

[0505]¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.51 (9H, s, t-Bu), 1.78 (6H, s,CH₃), 4.38 (2H, s, CH₂), 4.90 (2H, s, CH₂), 6.49 (1H, s, CH), 7.28 (1H,dd, J=2 Hz and J=8.0 Hz, aromatic), 7.41 (1H, d, J=8.0 Hz, aromatic),7.53 (1H, d, J=2.5 Hz, aromatic). Anal. calcd for C₂₀H₂₃Cl₂NO₇: C,52.19; H, 5.04; N, 3.04. Found: C, 52.25; H, 5.11; N, 2.93.

EXAMPLE 37

[0506] Compound 37-A: 4-Fluorobenzaldehyde O-(2-chloroethyl)-oxime

[0507] A suspension of sodium hydride (10.0 mmol, 0.40 g of a 60%suspension in mineral oil) in dry tetrahydrofuran (20 ml) was treated at25° C. with 1-bromo-2-chloroethane (2 ml, 23.8 mmol) followed by asolution of 4-fluorobenzaldehyde oxime (1.39 g, 10.0 mmol) intetrahydrofuran (20 ml) added dropwise over 10 min. The resultingmixture was then heated under reflux for 16 h. The cooled mixture wasdiluted with ethyl acetate, washed with brine and dried over anhydroussodium sulphate. Evaporation of the solvent under reduced pressure andchromatography of the residue on silica gel (elution hexane-ethylacetate, 8:2) gave 0.80 g (40% yield) of the title oxime as a clear oil.¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.81 (2H, t, J=6.0 Hz, CH₂), 4.4 (2H, t,J=6.0 Hz, CH₂), 7.10 (2H, m, aromatics), 7.60 (2H, m, aromatics), 8.13(1H, s, CH).

[0508] Compound 37-B: O-(2-Chloroethyl)-N-(4-fluorobenzyl)-hydroxylamine

[0509] Reduction of 4-fluorobenzaldehyde O-(2-chloroethyl)-oxime asdescribed in the preparation of compound 3-B gave the titlehydroxylamine as a clear oil (65% yield) after chromatography on silicagel (elution hexane-ethyl acetate, 7:3). ¹HNMR 400 MHz (C₆D₆) δ (ppm):3.31 (2H, t, J=6.0 Hz, CH₂), 3.61 (2H, t, J=6.0 Hz, CH₂), 3.65 (2H, s,NCH₂), 5.14 (1H, broad s, NH), 6.87 (2H, m, aromatics), 6.98 (2H, m,aromatics). The hydrochloride salt was obtained as a white solid. Anal.calcd for C₉H₁₁ClFNO—HCl: C, 53.08; H, 5.44; N, 6.88. Found: C, 53.17;H, 5.31; N, 7.07.

[0510] Compound 37-C:O-(2-Dimethylamino-ethyl)-N-(4-fluorobenzyl)-hydroxylamine

[0511] A solution of O-(2-chloroethyl)-N-(4-fluorobenzyl)-hydroxylamine(0.327 g, 1.6 mmol) in acetonitrile (2 ml) was treated with a solutionof dimethylamine (16 mmol, 8 ml of a 2 M solution in tetrahydrofuran).Sodium iodide (0.06 g) was then added and the resulting mixture wassealed and heated at 55° C. for 16 h. The cooled mixture was dilutedwith ethyl acetate, washed with saturated sodium bicarbonate, brine anddried over anhydrous sodium sulphate. Evaporation of the solvent underreduced pressure yielded 0.310 g (91% yield) of the crude titlehydroxylamine as a light brown oil which was used as such for the nextstep. ¹HNMR 400 MHz (C₆D₆) δ (ppm): 2.19 (6H, s, NCH₃), 2.47 (2H, t,J=6.1 Hz, CH₂), 3.82 (2H, s, NCH₂), 3.84 (2H, t, J=6.1 Hz, CH₂), 6.9(2H, m, aromatics), 7.11 (2H, m, aromatics).

[0512] Compound 37-D:N-(2-Dimethylamino-ethoxy)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-acetamide

[0513] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetylchloride with O-(2-dimethylamino-ethyl)-N-(4-fluorobenzyl)-hydroxylamineas described in the preparation of compound 1-A gave the title amide aswhite crystals (30% yield): mp 95-96° C. (ether-hexane).

[0514]¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 1.70 (6H, s, CH₃), 2.16 (6H, s,NCH₃), 2.44 (2H, t, J=5.3 Hz, CH₂), 3.97 (2H, t, J=5.3 Hz, CH₂), 4.79(2H, s, NCH₂), 6.52 (1H, s, CH), 7.18 (2H, m, aromatics), 7.34 (2H, m,aromatics). Anal. calcd for C₁₈H₂₃FN₂O₅: C, 59.00; H, 6.32; N, 7.64.Found: C, 58.73; H, 6.13; N, 7.40.

[0515] Compound 37:3-[(2-Dimethylamino-ethoxy)-(4-fluorobenzyl)-carbamoyl]-2-hydroxy-acrylicacid

[0516] Saponification ofN-(2-dimethylamino-ethoxy-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-(4-fluorobenzyl)-acetamideas described in the preparation of compound 1 gave the title material asa white powder after adjusting to pH 5 (1 N HCl), chromatography onreversed phase silica gel (Waters, C-18, 125 A) and freeze drying (68%yield).

[0517]¹HNMR 400 MHz (DMSO-d₆) δ (ppm): mainly keto form 2.73 (6H, s,NCH₃), 3.22 (2H, broad s, CH₂), 3.72 (2H, broad s, CH₂), 4.18 (2H, broads, OCH₂), 4.81 (2H, s, NCH₂), 7.17 (2H, m, aromatics), 7.38 (2H, m,aromatics). HRMS (MAB N₂) calculated for C₁₅H₁₉FN₂O₅[M⁺]: 326.127800:found: 326.127864. Anal. calcd for C₁₅H₁₉FN₂O₅—H₂O: C, 52.32; H, 6.15;N, 8.14. Found: C, 52.80; H, 5.79; N, 8.02.

EXAMPLE 38

[0518] Compound 38-A:[[2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl]-(4-fluoro-benzyl)-aminooxy]-acetylchloride

[0519] Compound 38-A was prepared from compound 22-A using the proceduredescribed in the preparation of compound 22-B.

[0520] Method for the preparation of compounds 38-61

[0521] Amine (0.165 mmol), VI-A in Scheme VI, was combined with2-(2-pyridyl)ethyl functionalized silica gel (0.38 mmol equivalents) in1 mL of 1,2-dichloroethane at 5° C. To this was added[[2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl]-(4-fluoro-benzyl)-aminooxy]-acetylchloride (0.165 mmol) dissolved in 1 mL of 1,2-dichloroethane. After 1hour at 25° C. the reaction mixture was filtered and purified on aShimadzu automated preparative HPLC system (Waters XTerra™ C-8, 5μ,19×100 mm, solvent A: Water 5mM NH₄OAC; Solvent B: Acetonitrile).

[0522] The collected compounds were analysed using the following LC/MSconditions. Column: X Terra 5μ C-8, 4.6 × 30 mm Solvent: Solvent A: 10%CH₃CN-90% H₂O, 5 mM NH₄Oac Solvent B: 90% CH₃CN-10% H₂O, 5 mM NH₄OacGradient: 100% solvent A/0% solvent B to 0% solvent A/100% solvent BGradient time: 2 minutes, hold time 1 minute. Flow rate: 4 ml/min.Detector wavelength 220 nm.

[0523] Compound retention times (RT) are recorded in the table below.Spectrometry (MS) data were determined with a Micromass ZMD Platform TSQ7000 LC/MS in positive electrospray mode. Results are reported in thetable below.

Compound X RT Formula MS 38

1.34 C₂₀H₂₃FN₂O₇ 423 39

1.95 C₃₄H₃₆FN₃O₆ 602 40

1.53 C₂₄H₂₆FN₅O₆ 500 41

1.69 C₂₄H₂₅FN₂O₆ 457 42

1.68 C₂₃H₂₂F₂N₂O₆ 461 43

1.75 C₂₃H₂₂ClFN₂O₆ 477 44

1.64 C₂₄H₂₅FN₂O₇ 473 45

1.71 C₂₄H₂₅FN₂O₆ 457 46

1.79 C₂₄H₂₂F₄N₂O₆ 511 47

1.72 C₂₄H₂₄F₂N₂O₆ 475 48

2.08 C₃₃H₃₃Cl₂FN₂O₆ 643 49

1.87 C₂₇H₃₁FN₂O₆ 499 50

1.72 C₂₃H₂₉FN₂O₆ 449 51

1.53 C₂₂H₂₇FN₂O₇ 451 52

1.48 C₂₁H₂₇FN₂O₈ 455 53

1.81 C₂₄H₃₃FN₂O₆ 465 54

2.08 C₂₈H₄₁FN₂O₆ 521 55

1.98 C₂₈H₃₇FN₂O₆ 517 56

1.53 C₂₁H₂₅FN₂O₈ 453 57

1.47 C₂₄H₂₆FN₃O₆ 472 58

1.49 C₂₂H₂₉FN₂O₈ 469 59

1.31 C₂₃H₂₈FN₃O₇ 478 60

1.43 C₁₈H₂₁FN₂O₆ 381 61

1.59 C₂₀H₂₅FN₂O₆ 409

EXAMPLE 39

[0524] Method for the preparation of compounds 62-79

[0525] Compounds 38-61 (0.05 mmol) were each dissolved in 2 mL of 1:1THF/H₂O and treated with 0.15 mL of 1M LiOH (in water) at 5° C. for 1.5hours. The reactions were quenched with 0.25 mL of 1M HCl. Afterevaporation of solvent the compounds were individually purified byfiltration through a Varian Bond Elute C-18 cartridge (Varian Inc. PaloAlto Calif.) using H₂O followed by 1:1-H₂O/acetonitrile to elute toproduct. Spectrometry (MS) data were determined with a Micromass ZMDPlatform TSQ 7000 LC/MS in negative electrospray mode.

Compound X Formula MS 62

C₁₇H₁₉FN₂O₇ 381 63

C₃₁H₃₂FN₃O₆ 560 64

C₂₁H₂₁FN₂O₆ 415 65

C₂₀H₁₈F₂N₂O₆ 419 66

C₂₀H₁₈ClFN₂O₆ 435 67

C₂₁H₂₁FN₂O₇ 431 68

C₂₁H₂₁FN₂O₆ 415 69

C₂₁H₁₈F₄N₂O₆ 469 70

C₂₁H₂₀F₂N₂O₆ 433 71

C₃₀H₂₉Cl₂FN₂O₆ 601 72

C₂₄H₂₇FN₂O₆ 457 73

C₂₀H₂₅FN₂O₆ 407 74

C₂₁H₂₉FN₂O₆ 423 75

C₂₅H₃₇FN₂O₆ 479 76

C₂₅H₃₃FN₂O₆ 475 77

C₂₀H₂₄FN₃O₇ 436 78

C₁₅H₁₇FN₂O₆ 339 79

C₁₇H₂₁FN₂O₆ 367

EXAMPLE 40

[0526] HIV-Integrase Inhibition Activity

[0527] The table below shows the percent inhibition of HIV-integrase inthe presence of 50 μM compounds 1-24 and 62-79. For each reaction, 5pmole of biotin labled substrate DNA was bound to 100 ug of Streptavidincoated PVT SPA beads (Amersham Pharmacia Biotech). 0.26 ng ofrecombinant integrase was incubated with the beads for 90 min at 37° C.Unbound enzyme was removed by washing the complex followed by additionof inhibitors and 0.1 fmol of P33 labeled target DNA. Reaction wasstopped by adding EDTA to a final concentration of 10 mM. Samples werecounted in TopCountNXT (Packard) and the CPM was used as a measure ofintegration. Reaction condition was as described in A. Engelman and R.Craigie, J. Virol. 69, 5908-5911 (1995). The sequences of substrate andtarget DNA were described in Nucleic Acid Research 22, 1121-1122 (1994).Compounds of this invention tested in this assay have IC₅₀'s ofapproximately 0.01 to 50 μM % inhibition Compound at 50 μM  1 99  2 99.9 3 99.9  4 99.9  5 99.9  6 99.9  7 99.9  8 99.9  9 99.9 10 99.9 11 99.912 99.9 13 99.9 14 99.9 15 99.0 16 99.0 17 99.9 18 96.0 19 99.9 20 99.921 99.9 22 99.9 23 65.0 24 99.9 62 >99% 63 >99% 64 >99% 65 >99% 66 >99%67 >99% 68 >99% 69 >99% 70 >99% 71 >99% 72 >99% 73 >99% 74 >99% 75 >99%76 >99% 77 >99% 78 >99% 79 >99%

[0528] Inhibition of HIV replication

[0529] Cell culture assays were preformed using a single cycle,recombinant HIV virus expressing Renella luciferase. Anti-viral activitywas evaluated by measuring the production of luciferase in the infectedcells 5 days post-infection. Susceptibility of the virus to compoundswas determined by incubation in the presence of the serially-dilutedcompound. The 50% effective concentration (EC₅₀) was calculated by usingthe exponential form of the median effect equation where(Fa)=1/[1+(ED₅₀/drug conc.)^(m)]. Compounds of this invention tested inthis assay have EC₅₀'s of approximately 0.02 to 50 μM. The table belowshows the percent viral inhbition at a compound concentration of 1.6 μMfor a set representative compounds. % Inhibition @ 1.6 Compound uM  3 96 4 90  5 96 15 33 31 47 3-C 96 4-B 87 5-B 94

EXAMPLE 41

[0530] Hydrolysis of Prodrugs Under Physiological Conditions

[0531] As shown in Scheme VII, compounds of Formula VII-A wherein R¹ andR² are as defined for Formula I, are hydrolyzed at pH 7 (37° C.) toyield the corresponding 2-hydroxy acrylic, VII-B, and are thus useful asprodrugs.

[0532] In an experiment to measure the hydrolysis of compounds such asVII-A, compound 3-C was added to 25mM phosphate buffer (pH 7) at aconcentration of 0.03 mg/mL. The reaction was incubated at 37° C. for aperiod of 24 hours. Interval time points are analyzed by HPLC,identifying both the compound 3-C and compound 3, the parent acid.Results are shown in the table. Hydrolysis of compound 3-C at pH 7 (37°C.) Compound 3-C Compound 3 Time (h) (mg/mL) (mg/mL) 0 0.026 0.001 0.50.022 0.008 1 0.017 0.012 1.5 0.013 0.014 2 0.010 0.016 4 0.003 0.021 60.001 0.022

We claim:
 1. A compound of formula I

wherein R¹ is -aryl, —C₁-C₆ alkyl-aryl, —C₁-C₆ alkyl-S(O)_(n)-aryl, or—C₁-C₅ alkyl-O-aryl; and wherein R¹ is unsubstituted or independentlysubstituted with 1-3 R³; Each R³ is independently selected from —H,-halo, —CN, —C₁-C₆ alkyl, —C₃-C₆ cycloalkyl —OR⁴, —C₁-C₁₀ alkyl-O—R⁴,—CO₂R⁵, —C₁-C₁₀ alkyl-CO₂R⁵, —N(R⁶)(R⁷), —C₁-C₁₀ alkyl-N(R⁶)(R⁷),—CON(R⁶)(R⁷), —C₁-C₁₀ alkyl-CON(R⁶)(R⁷) —S(O)_(n)R⁸, —-C₁₀alkyl-S(O)_(n)R⁸, —S(O)_(n)N(R⁹)(R¹⁰), —C₁-C₁₀ alkyl-S(O)_(n)N(R⁹)(R¹⁰),-aryl, —O-aryl, -heteroaryl, —O-heteroaryl, —C₁-C₆ alkyl-aryl, —C₁-C₆alkyl-heteroaryl, —C(O)-heterocyclic radical, —C₁-C₁₀alkyl-C(O)-heterocyclic radical, or —C₁-C₆ haloakyl; R² is —H, —C₁-C₁₀alkyl, —C₃-C₆ cycloakyl, —C₁-C₁₀ haloalkyl, -aryl, -heteroaryl, —C₁-C₆alkyl-aryl, —C₁-C₅ alkyl-O-aryl, —C₁-C₆ alkyl-heteroaryl, —C₁-C₅alkyl-O-heteroaryl, —C₁-C₁₀ alkyl-OR⁴, —C₁-C₁₀ alkyl-CO₂R⁵, —C₁-C₁₀alkyl-N(R⁶)(R⁷), —C₁-C₁₀ alkyl-CON(R⁶)(R⁷), —C₁-C₁₀ alkyl-S(O)_(n)R⁸,—C₁-C₁₀ alkyl-S(O)_(n)N(R⁹)(R¹⁰), or —C₁-C₁₀ alkyl-C(O)-heterocyclicradical; Each R⁴ is independently selected from —H —C₁-C₆ alkyl, —C₃-C₆cycloalkyl, —C₁-C₉ alkyl-CO₂R⁵, —C₁-C₉ alkyl-N(R⁶)(R⁷), —C₁-C₉alkyl-CON(R⁶)(R⁷), —C₁-C₉ alkyl-S(O)_(n)R⁸, or —C₁-C₉alkyl-S(O)_(n)N(R⁹)(R¹⁰); Each R⁵ is independently selected from —H,—C₁-C₆ alkyl, —C₃-C₆ cycloalkyl, or —C₁-C₆ alkyl-aryl; Each R⁶ isindependently selected from —H; —C₁-C₆ alkyl, -aryl, -heteroaryl, —C₁-C₆alkyl-aryl, —C₁-C₆ alkyl-heteroaryl, —C(O)—C₁-C₆ alkyl, —C(O)-aryl,—C(O)—C₁-C₆ alkyl-aryl, —C(O)-heteroaryl, —C(O)—C₁-C₆ alkyl-heteroaryl,—C(NH)NH₂, —S(O)_(n)—R⁸, or —C₁-C₆ alkyl-CO₂R⁵; Each R⁷ is independentlyselected from —H, —C₁-C₆ alkyl, -aryl, or -heteroaryl; Each R⁸ isindependently selected from —C₁-C₆ alkyl, -aryl, or -heteroaryl; Each R⁹is independently selected from —H, —C₁-C₆ alkyl, —C₁-C6 alkyl-aryl,—C₁-C₆ alkyl-heteroaryl, —C(O)—C₁-C₆ alkyl, —C(O)-aryl, —C(O)—C₁-C₆alkyl-aryl, —C(O)—C₁-C₆ alkyl-heteroaryl, -aryl, or -heteroaryl; EachR¹⁰ is independently selected from —H, —C₁-C₆ alkyl, —C₁-C₆ alkyl-aryl,—C₁-C₆ alkyl-heteroaryl, -aryl, or -heteroaryl; R¹¹ is —H, -aryl,-heteroaryl, —C₁-C₆ alkyl-heteroaryl, —C₃-C₆ cycloalkyl, —C₁-C₆ alkyl,—C₁-C₆ alkyl-aryl, —C₁-C₆ alkyl-CO₂R⁵, or —C₁-C₆ alkyl-N(R⁶)(R⁷); R¹² is—H, —C₁-C₆ alkyl, -aryl, or -heteroaryl; R¹³ is —H, —C₁-C₆ alkyl, -aryl,or -heteroaryl; and R¹² and R¹³ taken together may form a cyclic alkylketal; B¹ is selected from the group consisting of

n is 0, 1 or 2; or a pharmaceutically acceptable salt or solvatethereof.
 2. A compound of claim 1 wherein R¹ is -phenyl or —C₁-C₂alkyl-phenyl wherein the phenyl is unsubstituted or independentlysubstituted with 1-3 R³; Each R³ is independently selected from —H,-halo, —CN, —C₁-C₆alkyl, —OC₁-C₆alkyl, —CO₂R⁵, —N(R⁶)(R⁷), —CON(R⁶)(R⁷),-trifluoromethyl; R² is —C₁-C₆ alkyl, —CH₂-phenyl, —CH₂—CO₂R⁵,—C₁-C₂-alkyl-N(R⁶)(R⁷), —CH₂—CON(R⁶)(R⁷), —CH₂—C(O)-heterocyclicradical; R¹¹ is R⁵; R¹² and R¹³ are C₁-C₆ alkyl or can be taken togethermay form a cyclic alkyl ketal; B¹ is selected from the group consistingof


3. A compound of Formula I wherein R¹ is

in which R¹⁴, R^(14′) and R^(14″) are each independently selected fromcyano, hydrogen or halo; R² is C₁-C₂ alkyl or -H₂C(O)N(CH₃)₂; and B¹ is


4. A compound of claim 3 selected from the group consisting of:3-[(4-Fluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid;3-[(3,4-Difluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid;3-[(3-Bromo-4-fluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid;3-[(3-Cyano-4-fluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid;3-[(4-Fluoro-3-methyl-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid;3-[Ethoxy-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic acid.
 5. Acompound of the formula

or a pharmaceutically acceptable salt or solvate thereof.
 6. A compoundof the formula

or a pharmaceutically acceptable salt or solvate thereof.
 7. A compoundof the formula

or a pharmaceutically acceptable salt or solvate thereof.
 8. A compoundof the formula

or a pharmaceutically acceptable salt or solvate thereof.
 9. A compoundof the formula

or a pharmaceutically acceptable salt or solvate thereof.
 10. A compoundof the formula

or a pharmaceutically acceptable salt or solvate thereof.
 11. A compoundof the formula

or a pharmaceutically acceptable salt or solvate thereof.
 12. A compoundof formula I wherein R¹ is

in which R¹⁴, R^(14′) and R^(14″) are each independently selected fromcyano, hydrogen or halo; R² is C₁-C₂ alkyl or —CH₂C(O)N(CH₃)₂; and B¹ is

in which R¹² and R¹³ are each independently C₁-C₆ alkyl or takentogether form a cyclic alkyl ketal.
 13. A compound of claim 12 whereinR¹² and R¹³ are methyl.
 14. A compound of claim 13 selected from thegroup consisting of:2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide;N-(3,4-Difluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide;N-(3-Bromo-4-fluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide;N-(3-Cyano-4-fluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide;2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-Fluoro-3-methyl-benzyl)-N-methoxy-acetamide;2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-ethoxy-N-(4-fluoro-benzyl)-acetamide.15. A compound of the formula

or a pharmaceutically acceptable salt or solvate thereof.
 16. Acomposition useful for treating HIV infections comprising a therapeuticamount of a compound of claim 1 and a pharmaceutically acceptablecarrier.
 17. A pharmaceutical composition of claim 16, furthercomprising a therapeutically effective amount of one or more other HIVtreatment agents selected from (a) an HIV protease inhibitor, (b) anucleoside reverse transcriptase inhibitor, (c) a non-nucleoside reversetranscriptase inhibitor, (d) an HIV-entry inhibitor, (e) animmunomodulator, or a combination thereof.
 18. A method of inhibitingHIV integrase which comprises administering to a mammal in need of suchtreatment a therapeutically effective amount of a compound of claim 1,or a pharmaceutically acceptable salt or solvate thereof.
 19. A methodfor treating an HIV infection in a patient in need thereof, comprisingthe administration to such patient of a therapeutically effective amountof a compound of claim 1, or a pharmaceutically acceptable salt orsolvate thereof.